id: MODULE:acetylcholine_signaling title: Human acetylcholine transmission and comparative receptor mechanisms description: 'Human cholinergic transmission combines choline uptake by SLC5A7, cytosolic acetylcholine synthesis by CHAT, vesicular loading by SLC18A3, calcium-triggered exocytosis, receptor activation and extracellular acetylcholinesterase-mediated clearance. Nicotinic receptors are specific pentameric cation-channel assemblies: adult and fetal muscle receptors, neuronal heteromers, alpha7 homopentamers and alpha9/alpha10 heteromers. Their subunit requirements and ligand-binding interfaces differ. Muscarinic receptors activate heterotrimeric G proteins: M1/M3/M5 preferentially couple to Gq/11 and M2/M4 predominantly couple to Gi/o, with ligand, tissue and assay-dependent variation. GRKs and RGS proteins regulate signal duration. Channel calcium entry need not cause net excitation: alpha9/alpha10 activation in hair cells recruits calcium-sensitive potassium conductance. Optional rat and chicken receptor segments expose experimentally measured differences in calcium permeability and downstream calcium handling; they do not establish a complete conserved vertebrate circuit. Generic exocytosis and downstream PLC/cAMP pathways are explicit interfaces. Neuromuscular receptor clustering and synapse assembly are separate processes.' status: COMPLETE scope: CONCRETE evidence: - source_id: PW:0000841 title: acetylcholine signaling pathway statement: The module boundary follows the RGD Pathway Ontology term and its interactive diagram. The overview diagram draws ACh acting on nAChR and mAChR nodes and links out to the two subpathway diagrams; its record text describes CHAT synthesis from acetyl-CoA and choline, SLC18A3 vesicular loading, nicotinic and muscarinic reception, ACHE hydrolysis as signal termination and SLC5A7 reuptake of the resulting choline. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000841.yaml). - source_id: PW:0000842 title: acetylcholine signaling pathway via nicotinic acetylcholine receptor statement: The nicotinic subpathway diagram draws Chat, Slc18a3, released ACh, NMJ, postsynaptic and presynaptic nAChR nodes, Ache hydrolysis feeding choline back to synthesis through Slc5a7, and a separate cluster of Agrn-Lrp4, Lrp4-Musk, Dok7-Musk and NMJ nAChR-Rapsn associations with Musk positively affecting NMJ nAChR. The record text lists the subunit genes Chrna1-7, Chrna9-10, Chrnb1-4, Chrnd, Chrne and Chrng and describes the agrin/LRP4/MuSK/Dok7/rapsyn cluster as the prepatterning and stabilisation machinery that localises NMJ receptors. PW:0000842 has no GO mapping in the project's SSSOM file. - source_id: PW:0000843 title: acetylcholine signaling pathway via muscarinic acetylcholine receptor statement: The muscarinic subpathway diagram draws Chrm1, Chrm3 and Chrm5 associated with "Gnaq proteins in ACh" and Chrm2 and Chrm4 with "Gnai proteins in ACh", Galphaq signalling producing IP3 and DAG and Galphai signalling lowering cAMP, Adrbk1 (GRK2) negatively affecting all five receptors, Grk5 negatively affecting the presynaptic M2/M4 autoreceptors, Rgs2 negatively affecting the Gq proteins and Rgs4 and Rgs6 negatively affecting the Gi proteins, and presynaptic autoreceptor inhibition of ACh release. - source_id: GO:0095500 title: acetylcholine receptor signaling pathway statement: The GO mapping recorded for PW:0000841 in the project's module seeds (skos:relatedMatch); it covers the reception arm of the module. - source_id: GO:0007213 title: G protein-coupled acetylcholine receptor signaling pathway statement: The GO mapping recorded for PW:0000843 (skos:relatedMatch); it is the muscarinic branch, refined here into its PLC-activating (GO:0007207) and adenylate cyclase-inhibiting (GO:0007197) children. - source_id: PMID:10649566 title: Identification and characterization of the high-affinity choline transporter. statement: Original rat and nematode transporter work establishes high-affinity choline uptake. The human implementation is grounded separately in PMID:11027560; rate limitation is physiological-context dependent. supporting_text: In cholinergic neurons, high-affinity choline uptake in presynaptic terminals is the rate-limiting step in acetylcholine synthesis. - source_id: PMID:31073061 title: Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. statement: Establishes the two muscarinic coupling classes used as the variant axis of the muscarinic branch. supporting_text: M1R, M3R, and M5R couple to the Gq/ 11 family, whereas M2R and M4R couple to the Gi/ o family. - source_id: PMID:10869390 title: Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. statement: AChE is the principal terminator of cholinergic transmission. supporting_text: Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses - source_id: PMID:41461581 statement: Current authoritative nomenclature describes preferred coupling classes, not exclusive pairing in all physiological or experimental contexts. supporting_text: M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. notes: The human transmission boundary retains uptake, synthesis, VAChT loading, release, one or more complete receptor implementations, and AChE clearance. Generic exocytosis and PLC/cAMP effector machinery are referenced rather than duplicated; their full gene panels are outside this audit, while the exact VAChT interface member is reviewed. Nicotinic activity belongs to an assembled complex; alpha7 requires five copies of one product. Adult epsilon and fetal gamma are alternatives. Alpha5 and beta3 are accessory constituents of specific alternatives, not obligatory subunits of every neuronal receptor. Human alpha6-containing functional capacity is grounded in engineered concatamers; native composition is separately supported by comparative experiments and remains context dependent. Exact human selectors and same-taxon complex units prevent cross-species mixed assemblies. PANTHER classification records homology, not interchangeability or family-wide neurotransmitter specificity. Root taxa list sampled evidence; each required step is human, while rat/chicken parts are optional comparators and cannot satisfy the full human boundary. AGRN/LRP4/MUSK/DOK7/RAPSN receptor clustering remains in nmj_achr_clustering, not ACh reception. The 44-member audit includes all original 35 direct products, VAChT, human GNB5, three mouse cardiac comparators and four rat/chicken receptor comparators. The mouse Rgs6-Gnb5 regulator segment is explicit. G14 and Go coupling are separated from downstream effector claims; exact gene-product choices prevent substitution by other family members. Independent regulatory mechanisms are ONE_OR_MORE alternatives. Connections carry assay- and species-qualified evidence; no completed conserved circuit or universal native stoichiometry is claimed. Actual module Falcon and fallback attempts failed; research is based on normally cached publications and recorded manual assessment, with no fabricated provider report. module: id: acetylcholine_signaling label: Acetylcholine signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: acetylcholine receptor signaling pathway term: id: GO:0095500 label: acetylcholine receptor signaling pathway description: 'The reception arm: signalling initiated by ACh binding to nicotinic or muscarinic receptors. This is the GO term mapped to PW:0000841.' - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic description: Asserted alongside GO:0095500 because the RGD pathway also spans ACh synthesis, vesicular release and AChE clearance, which this term covers and the receptor signalling term does not. The two terms are not in a parent/child relation. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - preferred_term: Rattus norvegicus term: id: NCBITaxon:10116 label: Rattus norvegicus - preferred_term: Gallus gallus term: id: NCBITaxon:9031 label: Gallus gallus - preferred_term: Mus musculus term: id: NCBITaxon:10090 label: Mus musculus cellular_components: - preferred_term: cholinergic synapse term: id: GO:0098981 label: cholinergic synapse notes: The required transmission implementation is human. Root taxa enumerate the sampled evidence scope; rat/chicken receptor segments and mouse cardiac regulation are optional comparisons with their own taxon contexts, not complete alternative pathways or interchangeable cross-species units. parts: - order: 1 role: high-affinity choline uptake into the cholinergic terminal node: id: ach_choline_uptake label: CHT1 (SLC5A7) sodium-coupled choline uptake module_type: TRANSPORT_STEP description: SLC5A7 supplies extracellular choline for acetylcholine synthesis through sodium- and chloride-dependent high-affinity uptake. Uptake can limit synthesis under many physiological conditions; neither universal rate limitation nor neuron-exclusive expression is asserted. annotons: - id: slc5a7_choline_uptake label: CHT1 (SLC5A7) choline:sodium symport participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SLC5A7 (CHT1) term: id: UniProtKB:Q9GZV3 label: High affinity choline transporter 1 family: preferred_term: SLC5A7 (CHT1) lineage term: id: PANTHER:PTHR45897:SF2 label: HIGH AFFINITY CHOLINE TRANSPORTER 1 representative_members: - preferred_term: SLC5A7 (CHT1) term: id: UniProtKB:Q9GZV3 label: High affinity choline transporter 1 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/SLC5A7/SLC5A7-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: choline:sodium symporter activity term: id: GO:0005307 label: choline:sodium symporter activity substrates: - preferred_term: extracellular choline term: id: CHEBI:15354 label: choline processes: - preferred_term: choline transport term: id: GO:0015871 label: choline transport locations: - preferred_term: presynaptic membrane term: id: GO:0042734 label: presynaptic membrane role_description: Supplies choline to CHAT in the cholinergic terminal represented here. This localization is a module context, not an exclusion of other documented cellular compartments or tissues. evidence: - source_id: PMID:11027560 statement: Human CHT cloned from spinal cord produces saturable sodium/chloride-dependent choline uptake in COS-7 membrane vesicles. supporting_text: Expression of hCHT cDNA in COS-7 cells results in saturable, Na(+)/Cl(-)-dependent choline uptake - source_id: PMID:10649566 statement: Original comparative CHT1 characterization; the expression restriction reported here applies to its experimental context and is not a universal assertion about human SLC5A7. supporting_text: CHT1 is not homologous to neurotransmitter transporters, but is homologous to members of the Na+-dependent glucose transporter family. Expression of CHT1 mRNA is restricted to cholinergic neurons. - source_id: PMID:10649566 statement: Original comparative CHT1 characterization; the expression restriction reported here applies to its experimental context and is not a universal assertion about human SLC5A7. supporting_text: The characteristics of CHT1-mediated choline uptake essentially match those of high-affinity choline uptake in rat brain synaptosomes. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - order: 2 role: acetylcholine synthesis node: id: ach_synthesis label: CHAT synthesis of acetylcholine from acetyl-CoA and choline module_type: REACTION description: Cytosolic CHAT transfers the acetyl group of acetyl-CoA to choline, giving ACh and CoA; its presence defines a cholinergic neuron. annotons: - id: chat_ach_synthesis label: CHAT choline O-acetyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHAT term: id: UniProtKB:P28329 label: Choline O-acetyltransferase family: preferred_term: CHAT lineage term: id: PANTHER:PTHR22589:SF14 label: CHOLINE O-ACETYLTRANSFERASE representative_members: - preferred_term: CHAT term: id: UniProtKB:P28329 label: Choline O-acetyltransferase description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/CHAT/CHAT-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: choline O-acetyltransferase activity term: id: GO:0004102 label: choline O-acetyltransferase activity substrates: - preferred_term: acetyl-CoA term: id: CHEBI:15351 label: acetyl-CoA - preferred_term: choline term: id: CHEBI:15354 label: choline products: - preferred_term: acetylcholine term: id: CHEBI:15355 label: acetylcholine processes: - preferred_term: acetylcholine biosynthetic process term: id: GO:0008292 label: acetylcholine biosynthetic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: The only ACh-synthesising enzyme of cholinergic neurons; this matches the core function in the CHAT gene review. evidence: - source_id: PMID:17144655 statement: CHAT synthesises ACh from choline and acetyl-CoA. supporting_text: Choline acetyltransferase (ChAT) catalyzes the synthesis of the neurotransmitter acetylcholine from choline and acetyl-CoA, and its presence is a defining feature of cholinergic neurons. - source_id: PMID:11172068 statement: Catalytically impaired CHAT causes a congenital myasthenic syndrome with stimulation-dependent failure of neuromuscular transmission. supporting_text: Here we report that mutations in CHAT cause a congenital myasthenic syndrome associated with frequently fatal episodes of apnea (CMS-EA). context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - order: 3 role: vesicular acetylcholine loading node: id: ach_vesicle_loading label: VAChT (SLC18A3) loading of ACh into synaptic vesicles description: Included by reference to the VAChT variant of the synaptic vesicle neurotransmitter-loading module, which models SLC18A3 acetylcholine transmembrane transporter activity driven by the V-ATPase proton gradient. module_ref: synaptic_vesicle_neurotransmitter_loading#acetylcholine_loading context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - order: 4 role: calcium-triggered vesicular ACh release node: id: ach_release label: Synaptic vesicle exocytosis of ACh description: Included by reference to the synaptic vesicle exocytosis module (docking, priming and calcium-triggered SNARE fusion), which is transmitter-agnostic. module_ref: synaptic_vesicle_exocytosis context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - order: 5 role: acetylcholine reception node: id: ach_reception label: Nicotinic and muscarinic acetylcholine receptors module_type: SIGNALING_PATHWAY description: Released ACh binds ionotropic nicotinic receptors, which open a cation pore within milliseconds, and metabotropic muscarinic receptors, which activate heterotrimeric G proteins. A given synapse may use either class or both. variant_sets: - id: ach_receptor_class label: Receptor class axis: receptor class (ionotropic vs metabotropic) selection: ONE_OR_MORE notes: Many cholinergic targets, e.g. autonomic ganglia and hippocampal neurons, express both classes, hence ONE_OR_MORE. variants: - id: nicotinic_reception label: Nicotinic ACh receptor (ligand-gated cation channel) signalling module_type: SIGNALING_PATHWAY description: Pentameric ACh-gated cation channels assembled from specific subunit combinations. Each alternative is a complete channel, not a list of interchangeable subunits. Binding-site number and agonist occupancy requirements depend on composition. Inward cation current can depolarize a target, while alpha9/alpha10-mediated calcium entry can recruit potassium conductance and cause net hair-cell inhibition. variant_sets: - id: nachr_subtype label: Nicotinic receptor subtype axis: subunit composition / tissue selection: ONE_OR_MORE variants: - id: nachr_muscle_adult label: Adult human muscle nAChR module_type: PROTEIN_COMPLEX description: 'Human adult muscle receptor pentamer: two alpha1 subunits, one beta1, one delta and one epsilon. The complementary developmental subunit is an alternative, not an additional required unit. Canonical functional alpha1 is intended; the alpha-plus splice form is not inferred to assemble.' annotons: - id: nachr_muscle_adult_channel label: Adult human muscle nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Adult human muscle nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_muscle_adult_chrna1 label: alpha1 subunit (two copies) role: Principal (+) face of both ACh binding sites. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA1 term: id: UniProtKB:P02708 label: Acetylcholine receptor subunit alpha family: preferred_term: CHRNA1 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA1 term: id: UniProtKB:P02708 label: Acetylcholine receptor subunit alpha description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA1/CHRNA1-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_muscle_adult_chrnb1 label: beta1 subunit role: Non-binding structural subunit of the pentamer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB1 term: id: UniProtKB:P11230 label: Acetylcholine receptor subunit beta family: preferred_term: CHRNB1 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB1 term: id: UniProtKB:P11230 label: Acetylcholine receptor subunit beta description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB1/CHRNB1-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' - id: nachr_muscle_adult_chrnd label: delta subunit role: Complementary (-) face of one ACh site. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRND term: id: UniProtKB:Q07001 label: Acetylcholine receptor subunit delta family: preferred_term: CHRND nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRND term: id: UniProtKB:Q07001 label: Acetylcholine receptor subunit delta description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRND/CHRND-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' - id: nachr_muscle_adult_chrne label: epsilon subunit (adult) role: Complementary face of the second ACh site in adult receptors; confers short bursts and high conductance. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNE term: id: UniProtKB:Q04844 label: Acetylcholine receptor subunit epsilon family: preferred_term: CHRNE nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNE term: id: UniProtKB:Q04844 label: Acetylcholine receptor subunit epsilon description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNE/CHRNE-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: neuromuscular synaptic transmission term: id: GO:0007274 label: neuromuscular synaptic transmission locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane - preferred_term: neuromuscular junction term: id: GO:0031594 label: neuromuscular junction role_description: 'Human adult muscle receptor pentamer: two alpha1 subunits, one beta1, one delta and one epsilon. The complementary developmental subunit is an alternative, not an additional required unit. Canonical functional alpha1 is intended; the alpha-plus splice form is not inferred to assemble.' evidence: - source_id: PMID:8788941 statement: Human adult and fetal receptor compositions were compared by single-channel recording after expression in Xenopus oocytes; the alpha-plus splice form was not incorporated into functional channels. supporting_text: adult (alpha 2 beta delta epsilon) and fetal (alpha 2 beta delta gamma) context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_muscle_fetal label: Fetal human muscle nAChR module_type: PROTEIN_COMPLEX description: 'Human fetal muscle receptor pentamer: two alpha1 subunits, one beta1, one delta and one gamma. The complementary developmental subunit is an alternative, not an additional required unit. Canonical functional alpha1 is intended; the alpha-plus splice form is not inferred to assemble.' annotons: - id: nachr_muscle_fetal_channel label: Fetal human muscle nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Fetal human muscle nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_muscle_fetal_chrna1 label: alpha1 subunit (two copies) role: Principal (+) face of both ACh binding sites. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA1 term: id: UniProtKB:P02708 label: Acetylcholine receptor subunit alpha family: preferred_term: CHRNA1 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA1 term: id: UniProtKB:P02708 label: Acetylcholine receptor subunit alpha description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA1/CHRNA1-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_muscle_fetal_chrnb1 label: beta1 subunit role: Non-binding structural subunit of the pentamer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB1 term: id: UniProtKB:P11230 label: Acetylcholine receptor subunit beta family: preferred_term: CHRNB1 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB1 term: id: UniProtKB:P11230 label: Acetylcholine receptor subunit beta description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB1/CHRNB1-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' - id: nachr_muscle_fetal_chrnd label: delta subunit role: Complementary (-) face of one ACh site. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRND term: id: UniProtKB:Q07001 label: Acetylcholine receptor subunit delta family: preferred_term: CHRND nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRND term: id: UniProtKB:Q07001 label: Acetylcholine receptor subunit delta description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRND/CHRND-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' - id: nachr_muscle_fetal_chrng label: gamma subunit (fetal) role: Replaces epsilon in fetal receptors; longer openings, lower conductance. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNG term: id: UniProtKB:P07510 label: Acetylcholine receptor subunit gamma family: preferred_term: CHRNG nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNG term: id: UniProtKB:P07510 label: Acetylcholine receptor subunit gamma description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNG/CHRNG-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: neuromuscular synaptic transmission term: id: GO:0007274 label: neuromuscular synaptic transmission locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane - preferred_term: neuromuscular junction term: id: GO:0031594 label: neuromuscular junction role_description: 'Human fetal muscle receptor pentamer: two alpha1 subunits, one beta1, one delta and one gamma. The complementary developmental subunit is an alternative, not an additional required unit. Canonical functional alpha1 is intended; the alpha-plus splice form is not inferred to assemble.' evidence: - source_id: PMID:8788941 statement: Human adult and fetal receptor compositions were compared by single-channel recording after expression in Xenopus oocytes; the alpha-plus splice form was not incorporated into functional channels. supporting_text: adult (alpha 2 beta delta epsilon) and fetal (alpha 2 beta delta gamma) context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha4beta2_2_3 label: Human (alpha4)2(beta2)3 nAChR module_type: PROTEIN_COMPLEX description: Human alpha4/beta2 pentamer with 2 alpha4 and 3 beta2 subunits. Both stoichiometries are functional; agonist sensitivity, calcium permeability and binding interfaces differ. This composition does not require alpha2, alpha5, alpha6 or beta3. annotons: - id: nachr_alpha4beta2_2_3_channel label: Human (alpha4)2(beta2)3 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human (alpha4)2(beta2)3 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha4beta2_2_3_chrna4 label: alpha4 subunit role: Principal ACh-binding subunit of alpha4beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 family: preferred_term: CHRNA4 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA4/CHRNA4-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_alpha4beta2_2_3_chrnb2 label: beta2 subunit role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 family: preferred_term: CHRNB2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB2/CHRNB2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '3' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human alpha4/beta2 pentamer with 2 alpha4 and 3 beta2 subunits. Both stoichiometries are functional; agonist sensitivity, calcium permeability and binding interfaces differ. This composition does not require alpha2, alpha5, alpha6 or beta3. evidence: - source_id: PMID:27698419 statement: Direct human structural study isolates the 2alpha:3beta form and describes both established functional stoichiometries; its engineered intracellular-domain deletions are not native sequence evidence. supporting_text: The α4β2 receptor is known to assemble in two functional subunit stoichiometries, 3α:2β and 2α:3β. - source_id: PMID:32272141 statement: Structural review distinguishes the two stoichiometries and the additional alpha4/alpha4 binding interface in the alpha-rich form. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha4beta2_3_2 label: Human (alpha4)3(beta2)2 nAChR module_type: PROTEIN_COMPLEX description: Human alpha4/beta2 pentamer with 3 alpha4 and 2 beta2 subunits. Both stoichiometries are functional; agonist sensitivity, calcium permeability and binding interfaces differ. This composition does not require alpha2, alpha5, alpha6 or beta3. annotons: - id: nachr_alpha4beta2_3_2_channel label: Human (alpha4)3(beta2)2 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human (alpha4)3(beta2)2 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha4beta2_3_2_chrna4 label: alpha4 subunit role: Principal ACh-binding subunit of alpha4beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 family: preferred_term: CHRNA4 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA4/CHRNA4-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '3' - id: nachr_alpha4beta2_3_2_chrnb2 label: beta2 subunit role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 family: preferred_term: CHRNB2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB2/CHRNB2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human alpha4/beta2 pentamer with 3 alpha4 and 2 beta2 subunits. Both stoichiometries are functional; agonist sensitivity, calcium permeability and binding interfaces differ. This composition does not require alpha2, alpha5, alpha6 or beta3. evidence: - source_id: PMID:27698419 statement: Direct human structural study isolates the 2alpha:3beta form and describes both established functional stoichiometries; its engineered intracellular-domain deletions are not native sequence evidence. supporting_text: The α4β2 receptor is known to assemble in two functional subunit stoichiometries, 3α:2β and 2α:3β. - source_id: PMID:32272141 statement: Structural review distinguishes the two stoichiometries and the additional alpha4/alpha4 binding interface in the alpha-rich form. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha4beta2_alpha5 label: Human (alpha4beta2)2 alpha5 nAChR module_type: PROTEIN_COMPLEX description: Human alpha4/beta2/alpha5 pentamer with two alpha4, two beta2 and one accessory alpha5 subunit. Human subunits were examined with defined concatamers in Xenopus oocytes and stable human cell lines; the D398N alpha5 variant alters permeability and desensitization in a receptor-composition-dependent manner. annotons: - id: nachr_alpha4beta2_alpha5_channel label: Human (alpha4beta2)2 alpha5 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human (alpha4beta2)2 alpha5 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha4beta2_alpha5_chrna4 label: alpha4 subunit role: Principal ACh-binding subunit of alpha4beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 family: preferred_term: CHRNA4 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA4/CHRNA4-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_alpha4beta2_alpha5_chrnb2 label: beta2 subunit role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 family: preferred_term: CHRNB2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB2/CHRNB2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_alpha4beta2_alpha5_chrna5 label: alpha5 subunit role: Accessory subunit that speeds desensitisation. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA5 term: id: UniProtKB:P30532 label: Neuronal acetylcholine receptor subunit alpha-5 family: preferred_term: CHRNA5 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA5 term: id: UniProtKB:P30532 label: Neuronal acetylcholine receptor subunit alpha-5 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA5/CHRNA5-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human alpha4/beta2/alpha5 pentamer with two alpha4, two beta2 and one accessory alpha5 subunit. Human subunits were examined with defined concatamers in Xenopus oocytes and stable human cell lines; the D398N alpha5 variant alters permeability and desensitization in a receptor-composition-dependent manner. evidence: - source_id: PMID:20881005 statement: Defined human alpha4/beta2/alpha5 assemblies were functionally assayed; the accessory subunit is required for this alternative but not for alpha4/beta2-only channels. supporting_text: Oocytes were injected with 5 ng of the β2-α4-β2-α4 concatamer cRNA and 2.5 ng of α5 cRNA. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha2beta2 label: Human alpha2beta2 nAChR module_type: PROTEIN_COMPLEX description: Human alpha2 and beta2 form an ACh-responsive receptor in Xenopus oocytes. A pentameric receptor is intended, but no exact copy number or universal native neuronal localization is inferred from this expression experiment. annotons: - id: nachr_alpha2beta2_channel label: Human alpha2beta2 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human alpha2beta2 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha2beta2_chrna2 label: alpha2 subunit role: Alternative principal alpha subunit pairing with beta2 or beta4. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA2 term: id: UniProtKB:Q15822 label: Neuronal acetylcholine receptor subunit alpha-2 family: preferred_term: CHRNA2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA2 term: id: UniProtKB:Q15822 label: Neuronal acetylcholine receptor subunit alpha-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA2/CHRNA2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. - id: nachr_alpha2beta2_chrnb2 label: beta2 subunit role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 family: preferred_term: CHRNB2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB2/CHRNB2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human alpha2 and beta2 form an ACh-responsive receptor in Xenopus oocytes. A pentameric receptor is intended, but no exact copy number or universal native neuronal localization is inferred from this expression experiment. evidence: - source_id: PMID:8906617 statement: Human alpha2, alpha3 and alpha4 were each expressed with beta2 or beta4; these combinations gave antagonist-sensitive ACh-evoked currents. supporting_text: confirming functional expression of human nicotinic receptors. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha6beta2beta3 label: Human (alpha6beta2)2 beta3 nAChR module_type: PROTEIN_COMPLEX description: Human (alpha6beta2)2 beta3 channel capacity is grounded in defined concatamer expression. Native mouse immunoprecipitation/knockout evidence supports related alpha6-containing assemblies, but does not establish this precise human native arrangement. Simple alpha6 plus beta2 alone is not asserted sufficient; beta3 is a required accessory unit in this modeled implementation. annotons: - id: nachr_alpha6beta2beta3_channel label: Human (alpha6beta2)2 beta3 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human (alpha6beta2)2 beta3 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha6beta2beta3_chrna6 label: alpha6 subunit role: Principal subunit of presynaptic alpha6beta2* receptors. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA6 term: id: UniProtKB:Q15825 label: Neuronal acetylcholine receptor subunit alpha-6 family: preferred_term: CHRNA6 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA6 term: id: UniProtKB:Q15825 label: Neuronal acetylcholine receptor subunit alpha-6 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA6/CHRNA6-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_alpha6beta2beta3_chrnb2 label: beta2 subunit role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 family: preferred_term: CHRNB2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB2/CHRNB2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_alpha6beta2beta3_chrnb3 label: beta3 subunit role: Accessory subunit of alpha6beta2beta3 receptors. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB3 term: id: UniProtKB:Q05901 label: Neuronal acetylcholine receptor subunit beta-3 family: preferred_term: CHRNB3 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB3 term: id: UniProtKB:Q05901 label: Neuronal acetylcholine receptor subunit beta-3 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB3/CHRNB3-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic - preferred_term: presynaptic modulation of chemical synaptic transmission term: id: GO:0099171 label: presynaptic modulation of chemical synaptic transmission locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human (alpha6beta2)2 beta3 channel capacity is grounded in defined concatamer expression. Native mouse immunoprecipitation/knockout evidence supports related alpha6-containing assemblies, but does not establish this precise human native arrangement. Simple alpha6 plus beta2 alone is not asserted sufficient; beta3 is a required accessory unit in this modeled implementation. evidence: - source_id: PMID:20923852 statement: Human concatameric subunits permit functional alpha6/beta2/beta3-containing receptors with defined compositions; native unlinked assembly and surface delivery remain distinct questions. supporting_text: Concatameric subunits permit assembly of functional α6β2β3* AChRs with defined subunit compositions and subunit orders. - source_id: PMID:12944511 statement: Mouse striatal immunoprecipitation and knockout studies establish related alpha6-containing receptor classes; these are comparative native evidence, not direct human stoichiometry measurements. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha4alpha6beta2beta3 label: Human (alpha4beta2)(alpha6beta2) beta3 nAChR module_type: PROTEIN_COMPLEX description: Human (alpha4beta2)(alpha6beta2) beta3 channel capacity is grounded in defined concatamer expression. Native mouse immunoprecipitation/knockout evidence supports related alpha6-containing assemblies, but does not establish this precise human native arrangement. Simple alpha6 plus beta2 alone is not asserted sufficient; beta3 is a required accessory unit in this modeled implementation. annotons: - id: nachr_alpha4alpha6beta2beta3_channel label: Human (alpha4beta2)(alpha6beta2) beta3 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human (alpha4beta2)(alpha6beta2) beta3 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha4alpha6beta2beta3_chrna4 label: alpha4 subunit role: Principal ACh-binding subunit of alpha4beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 family: preferred_term: CHRNA4 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA4 term: id: UniProtKB:P43681 label: Neuronal acetylcholine receptor subunit alpha-4 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA4/CHRNA4-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' - id: nachr_alpha4alpha6beta2beta3_chrna6 label: alpha6 subunit role: Principal subunit of presynaptic alpha6beta2* receptors. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA6 term: id: UniProtKB:Q15825 label: Neuronal acetylcholine receptor subunit alpha-6 family: preferred_term: CHRNA6 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA6 term: id: UniProtKB:Q15825 label: Neuronal acetylcholine receptor subunit alpha-6 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA6/CHRNA6-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' - id: nachr_alpha4alpha6beta2beta3_chrnb2 label: beta2 subunit role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 family: preferred_term: CHRNB2 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB2 term: id: UniProtKB:P17787 label: Neuronal acetylcholine receptor subunit beta-2 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB2/CHRNB2-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '2' - id: nachr_alpha4alpha6beta2beta3_chrnb3 label: beta3 subunit role: Accessory subunit of alpha6beta2beta3 receptors. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB3 term: id: UniProtKB:Q05901 label: Neuronal acetylcholine receptor subunit beta-3 family: preferred_term: CHRNB3 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB3 term: id: UniProtKB:Q05901 label: Neuronal acetylcholine receptor subunit beta-3 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB3/CHRNB3-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: '1' function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic - preferred_term: presynaptic modulation of chemical synaptic transmission term: id: GO:0099171 label: presynaptic modulation of chemical synaptic transmission locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human (alpha4beta2)(alpha6beta2) beta3 channel capacity is grounded in defined concatamer expression. Native mouse immunoprecipitation/knockout evidence supports related alpha6-containing assemblies, but does not establish this precise human native arrangement. Simple alpha6 plus beta2 alone is not asserted sufficient; beta3 is a required accessory unit in this modeled implementation. evidence: - source_id: PMID:20923852 statement: Human concatameric subunits permit functional alpha6/beta2/beta3-containing receptors with defined compositions; native unlinked assembly and surface delivery remain distinct questions. supporting_text: Concatameric subunits permit assembly of functional α6β2β3* AChRs with defined subunit compositions and subunit orders. - source_id: PMID:12944511 statement: Mouse striatal immunoprecipitation and knockout studies establish related alpha6-containing receptor classes; these are comparative native evidence, not direct human stoichiometry measurements. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha3beta4_base label: Human alpha3beta4 nAChR module_type: PROTEIN_COMPLEX description: Human alpha3/beta4 receptor assembled in Xenopus oocytes. Alpha5 is unnecessary for this base alternative; its inclusion is represented separately. Native mouse autonomic evidence supports the subtype class, without making every ganglionic pentamer identical. annotons: - id: nachr_alpha3beta4_base_channel label: Human alpha3beta4 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human alpha3beta4 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha3beta4_base_chrna3 label: alpha3 subunit role: Principal ACh-binding subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA3 term: id: UniProtKB:P32297 label: Neuronal acetylcholine receptor subunit alpha-3 family: preferred_term: CHRNA3 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA3 term: id: UniProtKB:P32297 label: Neuronal acetylcholine receptor subunit alpha-3 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA3/CHRNA3-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. - id: nachr_alpha3beta4_base_chrnb4 label: beta4 subunit role: Complementary ACh-site subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB4 term: id: UniProtKB:P30926 label: Neuronal acetylcholine receptor subunit beta-4 family: preferred_term: CHRNB4 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB4 term: id: UniProtKB:P30926 label: Neuronal acetylcholine receptor subunit beta-4 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB4/CHRNB4-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: Human alpha3/beta4 receptor assembled in Xenopus oocytes. Alpha5 is unnecessary for this base alternative; its inclusion is represented separately. Native mouse autonomic evidence supports the subtype class, without making every ganglionic pentamer identical. evidence: - source_id: PMID:8663494 statement: Cloned human alpha3/beta4 with or without alpha5 reaches the oocyte surface and yields functional receptors; alpha5 speeds desensitization. supporting_text: alpha5 subunits coassembled very efficiently with alpha3beta2 or alpha3beta4 combinations. - source_id: PMID:10531434 statement: Native mouse beta-subunit knockouts establish the importance of beta4-containing receptors in autonomic ganglia; this is not a direct human copy-number measurement. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha3beta4_alpha5 label: Human alpha3beta4alpha5 nAChR module_type: PROTEIN_COMPLEX description: Human alpha3/beta4/alpha5 receptor assembled in Xenopus oocytes. Alpha5 is a constituent of this alternative and changes desensitization; it is not obligatory for every alpha3beta4 receptor. Native mouse autonomic evidence supports the subtype class, without making every ganglionic pentamer identical. annotons: - id: nachr_alpha3beta4_alpha5_channel label: Human alpha3beta4alpha5 nAChR cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Human alpha3beta4alpha5 nAChR term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: nachr_alpha3beta4_alpha5_chrna3 label: alpha3 subunit role: Principal ACh-binding subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA3 term: id: UniProtKB:P32297 label: Neuronal acetylcholine receptor subunit alpha-3 family: preferred_term: CHRNA3 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA3 term: id: UniProtKB:P32297 label: Neuronal acetylcholine receptor subunit alpha-3 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA3/CHRNA3-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. - id: nachr_alpha3beta4_alpha5_chrnb4 label: beta4 subunit role: Complementary ACh-site subunit. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNB4 term: id: UniProtKB:P30926 label: Neuronal acetylcholine receptor subunit beta-4 family: preferred_term: CHRNB4 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNB4 term: id: UniProtKB:P30926 label: Neuronal acetylcholine receptor subunit beta-4 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNB4/CHRNB4-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. - id: nachr_alpha3beta4_alpha5_chrna5 label: alpha5 subunit role: Accessory subunit that speeds desensitisation. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA5 term: id: UniProtKB:P30532 label: Neuronal acetylcholine receptor subunit alpha-5 family: preferred_term: CHRNA5 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA5 term: id: UniProtKB:P30532 label: Neuronal acetylcholine receptor subunit alpha-5 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA5/CHRNA5-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. stoichiometry: 1 accessory subunit in the modeled pentamer function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: synaptic transmission, cholinergic term: id: GO:0007271 label: synaptic transmission, cholinergic locations: - preferred_term: postsynaptic membrane term: id: GO:0045211 label: postsynaptic membrane role_description: Human alpha3/beta4/alpha5 receptor assembled in Xenopus oocytes. Alpha5 is a constituent of this alternative and changes desensitization; it is not obligatory for every alpha3beta4 receptor. Native mouse autonomic evidence supports the subtype class, without making every ganglionic pentamer identical. evidence: - source_id: PMID:8663494 statement: Cloned human alpha3/beta4 with or without alpha5 reaches the oocyte surface and yields functional receptors; alpha5 speeds desensitization. supporting_text: alpha5 subunits coassembled very efficiently with alpha3beta2 or alpha3beta4 combinations. - source_id: PMID:10531434 statement: Native mouse beta-subunit knockouts establish the importance of beta4-containing receptors in autonomic ganglia; this is not a direct human copy-number measurement. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha7 label: Homomeric alpha7 nAChR module_type: PROTEIN_COMPLEX description: The channel implementation is a calcium-permeable alpha7 homopentamer with five copies of CHRNA7. Alpha7-dependent non-neuronal and immune signaling can proceed through non-ionotropic mechanisms and is not equated with this conductive implementation. annotons: - id: alpha7_nachr_channel label: alpha7 nAChR ACh-gated cation channel participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: human alpha7 homopentamer term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: human_alpha7_unit label: alpha7 subunit stoichiometry: '5' role: Five identical subunits form the ligand-binding interfaces and central cation pore. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA7 term: id: UniProtKB:P36544 label: Neuronal acetylcholine receptor subunit alpha-7 family: preferred_term: CHRNA7 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA7 term: id: UniProtKB:P36544 label: Neuronal acetylcholine receptor subunit alpha-7 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA7/CHRNA7-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: acetylcholine receptor signaling pathway term: id: GO:0095500 label: acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: The assembled alpha7 homopentamer carries the channel activity. One gene supplies all five copies; a monomer is not represented as a complete pore. Ligand-site count does not specify how many sites must be occupied for opening. evidence: - source_id: PMID:8906617 statement: Human alpha7 alone forms a functional ACh-gated receptor. supporting_text: Recombinant receptors were expressed in Xenopus laevis oocytes injected with in vitro transcripts encoding either alpha 7 alone or alpha 2, alpha 3, or alpha 4 in pairwise combination with beta 2 or beta 4. gocam_associations: - model: gomodel:678073a900000353 activity: gomodel:678073a900000353/678073a900000357 title: CHRNA7 nAChR activity in synaptic transmission involved in micturition. (Human) description: CHRNA7 acetylcholine-gated monoatomic cation-selective channel activity (GO:0022848) part of acetylcholine receptor signaling pathway (GO:0095500); the project's best-overlap GO-CAM for PW:0000841. - model: gomodel:67369e7600000404 activity: gomodel:67369e7600000404/67369e7600000405 title: CHRNA7 homopentameric ligand-gated cation channel activated by Acetylcholine (Human). description: Same gene and molecular function, with ACh as the activating ligand. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - id: nachr_alpha9alpha10 label: alpha9alpha10 nAChR module_type: PROTEIN_COMPLEX description: Human alpha9/alpha10 ACh-gated cation-channel heteromer, directly tested in expression systems. Hair-cell inhibition is a downstream cellular response involving calcium-sensitive potassium conductance; it is not the sign of the receptor cation current itself. annotons: - id: alpha9alpha10_nachr_channel label: alpha9alpha10 nAChR ACh-gated cation channel participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: alpha9alpha10 nicotinic receptor term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: chrna9_unit label: alpha9 subunit role: ACh-binding subunit; can form homomers in heterologous expression. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA9 term: id: UniProtKB:Q9UGM1 label: Neuronal acetylcholine receptor subunit alpha-9 family: preferred_term: CHRNA9 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA9 term: id: UniProtKB:Q9UGM1 label: Neuronal acetylcholine receptor subunit alpha-9 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA9/CHRNA9-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. - id: chrna10_unit label: alpha10 subunit role: Partner subunit required for the native heteromer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA10 term: id: UniProtKB:Q9GZZ6 label: Neuronal acetylcholine receptor subunit alpha-10 family: preferred_term: CHRNA10 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA10 term: id: UniProtKB:Q9GZZ6 label: Neuronal acetylcholine receptor subunit alpha-10 description: Classification of the named subunit exemplar. The broad PANTHER family also contains other ligand-gated channels; neither acetylcholine specificity nor replacement of this particular subunit is asserted for the whole family. evidence: - source_id: file:human/CHRNA10/CHRNA10-uniprot.txt statement: The curated record assigns this exact exemplar to PANTHER PTHR18945. function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: acetylcholine receptor signaling pathway term: id: GO:0095500 label: acetylcholine receptor signaling pathway role_description: Human alpha9/alpha10 ACh-gated cation-channel heteromer, directly tested in expression systems. Hair-cell inhibition is a downstream cellular response involving calcium-sensitive potassium conductance; it is not the sign of the receptor cation current itself. gocam_associations: - model: gomodel:67b1629100004300 activity: gomodel:67b1629100004300/67b1629100004304 title: CHRNA9 nAChR sodium channel activity. (Human) description: CHRNA9 acetylcholine-gated monoatomic cation-selective channel activity (GO:0022848) part of acetylcholine receptor signaling pathway; sibling models gomodel:67b1629100004130 and gomodel:67b1629100004322 model its potassium and calcium permeation. evidence: - source_id: PMID:11752216 statement: Cloned human alpha9 and alpha10 form functional ACh-responsive receptors; the experiment grounds the human channel, while native hair-cell physiology requires separate evidence. - source_id: PMID:34867208 statement: Review distinguishes receptor calcium entry from recruitment of the nearby SK2 potassium channel and net hair-cell inhibition. supporting_text: secondary activation of a nearby calcium-dependent SK2 potassium channel context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens evidence: - source_id: PMID:32272141 statement: Structural review supports limited subunit combinations, composition-dependent binding interfaces and channel properties. supporting_text: assemble in limited combinations - source_id: PMID:34867208 statement: Alpha9/alpha10-mediated hair-cell signaling separates cation influx from downstream inhibition. - id: muscarinic_reception label: Muscarinic ACh receptor (GPCR) signalling module_type: SIGNALING_PATHWAY description: ACh-occupied muscarinic receptors activate heterotrimeric G proteins. M1/M3/M5 favor Gq/11 and M2/M4 favor Gi/o; these are predominant coupling classes rather than exclusive pairings under all ligands and expression contexts. concepts: - preferred_term: G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007213 label: G protein-coupled acetylcholine receptor signaling pathway variant_sets: - id: machr_coupling label: Muscarinic G protein coupling class axis: G protein family coupled selection: ONE_OR_MORE variants: - id: machr_gq_branch label: M1/M3/M5 -> Gq/11 -> PLC beta module_type: SIGNALING_PATHWAY concepts: - preferred_term: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007207 label: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway parts: - order: 1 role: receptor and Gq/11 activation node: id: machr_gq_activation label: M1/M3/M5 activate G alpha q/11 module_type: REGULATORY_STEP parts: - order: 1 role: M1/M3/M5 G protein-coupled ACh receptors node: id: m1_m3_m5_receptor label: M1/M3/M5 G protein-coupled ACh receptors module_type: REGULATORY_STEP description: 'Postsynaptic and effector-tissue receptors: M1 in cortex and hippocampus, M3 in smooth muscle and glands, M5 on midbrain dopamine neurons. The representative members are the three human subtypes, not a PANTHER family claim. Exact member alternatives enforce the selected receptor/G-protein subset; attached PANTHER descriptors record classification only.' variant_sets: - id: m1_m3_m5_receptor_member_choices label: Named member alternatives axis: gene product selection: ONE_OR_MORE variants: - id: m1_m3_m5_receptor_chrm1_implementation label: CHRM1 annotons: - id: m1_m3_m5_receptor_chrm1 label: CHRM1 — M1/M3/M5 G protein-coupled ACh receptors participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM1 (M1) term: id: UniProtKB:P11229 label: Muscarinic acetylcholine receptor M1 family: preferred_term: CHRM1 lineage term: id: PANTHER:PTHR24247:SF182 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M1 representative_members: - preferred_term: CHRM1 (M1) term: id: UniProtKB:P11229 label: Muscarinic acetylcholine receptor M1 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM1/CHRM1-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007207 label: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: 'Postsynaptic and effector-tissue receptors: M1 in cortex and hippocampus, M3 in smooth muscle and glands, M5 on midbrain dopamine neurons. The representative members are the three human subtypes, not a PANTHER family claim.' evidence: - source_id: PMID:31073061 statement: M1, M3 and M5 couple to Gq/11. supporting_text: M1R, M3R, and M5R couple to the Gq/ 11 family - source_id: PMID:8508928 statement: The human M1 receptor activates both Gq alpha and G11 alpha. supporting_text: These data indicate that the HM1 receptor interacts with the activates both Gq alpha and G11 alpha equivalently and non-selectively in a whole cell system in which the receptor has access to both G-proteins. - id: m1_m3_m5_receptor_chrm3_implementation label: CHRM3 annotons: - id: m1_m3_m5_receptor_chrm3 label: CHRM3 — M1/M3/M5 G protein-coupled ACh receptors participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM3 (M3) term: id: UniProtKB:P20309 label: Muscarinic acetylcholine receptor M3 family: preferred_term: CHRM3 lineage term: id: PANTHER:PTHR24247:SF183 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M3 representative_members: - preferred_term: CHRM3 (M3) term: id: UniProtKB:P20309 label: Muscarinic acetylcholine receptor M3 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM3/CHRM3-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007207 label: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: 'Postsynaptic and effector-tissue receptors: M1 in cortex and hippocampus, M3 in smooth muscle and glands, M5 on midbrain dopamine neurons. The representative members are the three human subtypes, not a PANTHER family claim.' evidence: - source_id: PMID:31073061 statement: M1, M3 and M5 couple to Gq/11. supporting_text: M1R, M3R, and M5R couple to the Gq/ 11 family - source_id: PMID:8508928 statement: The human M1 receptor activates both Gq alpha and G11 alpha. supporting_text: These data indicate that the HM1 receptor interacts with the activates both Gq alpha and G11 alpha equivalently and non-selectively in a whole cell system in which the receptor has access to both G-proteins. - id: m1_m3_m5_receptor_chrm5_implementation label: CHRM5 annotons: - id: m1_m3_m5_receptor_chrm5 label: CHRM5 — M1/M3/M5 G protein-coupled ACh receptors participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM5 (M5) term: id: UniProtKB:P08912 label: Muscarinic acetylcholine receptor M5 family: preferred_term: CHRM5 lineage term: id: PANTHER:PTHR24247:SF209 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M5 representative_members: - preferred_term: CHRM5 (M5) term: id: UniProtKB:P08912 label: Muscarinic acetylcholine receptor M5 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM5/CHRM5-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007207 label: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: 'Postsynaptic and effector-tissue receptors: M1 in cortex and hippocampus, M3 in smooth muscle and glands, M5 on midbrain dopamine neurons. The representative members are the three human subtypes, not a PANTHER family claim.' evidence: - source_id: PMID:31073061 statement: M1, M3 and M5 couple to Gq/11. supporting_text: M1R, M3R, and M5R couple to the Gq/ 11 family - source_id: PMID:8508928 statement: The human M1 receptor activates both Gq alpha and G11 alpha. supporting_text: These data indicate that the HM1 receptor interacts with the activates both Gq alpha and G11 alpha equivalently and non-selectively in a whole cell system in which the receptor has access to both G-proteins. gocam_associations: - model: gomodel:62f58d8800003672 activity: gomodel:62f58d8800003672/62f58d8800003680 title: Positive regulation of insulin secretion 3 (Mouse) description: Mouse Chrm3 G protein-coupled acetylcholine receptor activity (GO:0016907) in the PLC-activating ACh receptor pathway (GO:0007207) of the beta cell; same function and process, orthologous gene. - order: 2 role: G alpha q/11 family switch node: id: g_alpha_q_11 label: G alpha q/11 family switch module_type: REGULATORY_STEP description: GTP-bound Gq/11 stimulates PLC beta. GNA14 is retained in a separate muscarinic coupling segment because receptor/G-protein activation and downstream PLC assays establish distinct claims. Exact member alternatives enforce the selected receptor/G-protein subset; attached PANTHER descriptors record classification only. variant_sets: - id: g_alpha_q_11_member_choices label: Named member alternatives axis: gene product selection: ONE_OR_MORE variants: - id: g_alpha_q_11_gnaq_implementation label: GNAQ annotons: - id: g_alpha_q_11_gnaq label: GNAQ — G alpha q/11 family switch participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha family: preferred_term: GNAQ lineage term: id: PANTHER:PTHR10218:SF329 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(Q) SUBUNIT ALPHA representative_members: - preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/GNAQ/GNAQ-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007207 label: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: GTP-bound Gq/11 stimulates PLC beta. GNA14 is retained in a separate muscarinic coupling segment because receptor/G-protein activation and downstream PLC assays establish distinct claims. evidence: - source_id: PMID:31073061 statement: The M1 receptor was solved in complex with G11. supporting_text: Here, we present and compare the cryo-electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA - id: g_alpha_q_11_gna11_implementation label: GNA11 annotons: - id: g_alpha_q_11_gna11 label: GNA11 — G alpha q/11 family switch participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNA11 term: id: UniProtKB:P29992 label: Guanine nucleotide-binding protein subunit alpha-11 family: preferred_term: GNA11 lineage term: id: PANTHER:PTHR10218:SF328 label: GUANINE NUCLEOTIDE-BINDING PROTEIN SUBUNIT ALPHA-11 representative_members: - preferred_term: GNA11 term: id: UniProtKB:P29992 label: Guanine nucleotide-binding protein subunit alpha-11 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/GNA11/GNA11-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007207 label: phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: GTP-bound Gq/11 stimulates PLC beta. GNA14 is retained in a separate muscarinic coupling segment because receptor/G-protein activation and downstream PLC assays establish distinct claims. evidence: - source_id: PMID:31073061 statement: The M1 receptor was solved in complex with G11. supporting_text: Here, we present and compare the cryo-electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA gocam_associations: - model: gomodel:62f58d8800003672 activity: gomodel:62f58d8800003672/62f58d8800003678 title: Positive regulation of insulin secretion 3 (Mouse) description: Mouse Gnaq G protein activity (GO:0003925) downstream of Chrm3 in GO:0007207; the same model has Gna11 as gomodel:62f58d8800003672/62f58d8800003699. - order: 2 role: PLC beta, IP3/calcium and DAG/PKC effector cascade node: id: machr_gq_plc_effector label: PLC beta hydrolysis of PIP2 (shared Gq effector) description: Included by reference to the PLC beta step of the generic Gq-PLC-calcium-PKC module; the downstream IP3/calcium and DAG/PKC steps are in the same module. module_ref: gpcr_plc_calcium_pkc_signaling#plc_beta_activation connections: - source: machr_gq_activation target: machr_gq_plc_effector connection_type: POSITIVELY_REGULATES description: Activated Gq/11 connects muscarinic reception to the PLC-beta effector interface. Purified M1/Gq/PLC-beta1 reconstitution establishes the mechanism, with human receptor coupling supported separately; the abstract does not establish that every reconstituted protein was human. evidence: - source_id: PMID:8626481 statement: Purified receptor/Gq/PLC-beta1 vesicle reconstitution requires agonist and GTP for PLC activation. supporting_text: Both GTP and agonist were required for PLC activation - source_id: PMID:8508928 statement: Human M1 expressed in CHO cells engages endogenous Gq and G11; these host G proteins are not represented as human construct measurements. - id: machr_gi_branch label: M2/M4 Gi signaling and inhibitory cAMP output module_type: SIGNALING_PATHWAY concepts: - preferred_term: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007197 label: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway parts: - order: 1 role: receptor and Gi/o activation node: id: machr_gi_activation label: M2/M4 activate G alpha i/o module_type: REGULATORY_STEP parts: - order: 1 role: M2/M4 G protein-coupled ACh receptors node: id: m2_m4_receptor label: M2/M4 G protein-coupled ACh receptors module_type: REGULATORY_STEP description: M2 slows the heart and, with M4, acts as the presynaptic autoreceptor that inhibits ACh release. Exact member alternatives enforce the selected receptor/G-protein subset; attached PANTHER descriptors record classification only. variant_sets: - id: m2_m4_receptor_member_choices label: Named member alternatives axis: gene product selection: ONE_OR_MORE variants: - id: m2_m4_receptor_chrm2_implementation label: CHRM2 annotons: - id: m2_m4_receptor_chrm2 label: CHRM2 — M2/M4 G protein-coupled ACh receptors participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM2 (M2) term: id: UniProtKB:P08172 label: Muscarinic acetylcholine receptor M2 family: preferred_term: CHRM2 lineage term: id: PANTHER:PTHR24247:SF207 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M2 representative_members: - preferred_term: CHRM2 (M2) term: id: UniProtKB:P08172 label: Muscarinic acetylcholine receptor M2 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM2/CHRM2-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007197 label: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: M2 slows the heart and, with M4, acts as the presynaptic autoreceptor that inhibits ACh release. evidence: - source_id: PMID:31073061 statement: M2 and M4 couple to Gi/o. supporting_text: whereas M2R and M4R couple to the Gi/ o family - source_id: PMID:19478075 statement: Presynaptic M2/M4 autoreceptors restrain ACh release, and the restraint is pertussis-toxin (Gi/o) sensitive. supporting_text: This reduction was fully corrected by pertussis toxin, atropine (a nonselective muscarinic antagonist), or methoctramine (a selective M2/M4 muscarinic receptor antagonist). - id: m2_m4_receptor_chrm4_implementation label: CHRM4 annotons: - id: m2_m4_receptor_chrm4 label: CHRM4 — M2/M4 G protein-coupled ACh receptors participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM4 (M4) term: id: UniProtKB:P08173 label: Muscarinic acetylcholine receptor M4 family: preferred_term: CHRM4 lineage term: id: PANTHER:PTHR24247:SF180 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M4 representative_members: - preferred_term: CHRM4 (M4) term: id: UniProtKB:P08173 label: Muscarinic acetylcholine receptor M4 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM4/CHRM4-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007197 label: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: M2 slows the heart and, with M4, acts as the presynaptic autoreceptor that inhibits ACh release. evidence: - source_id: PMID:31073061 statement: M2 and M4 couple to Gi/o. supporting_text: whereas M2R and M4R couple to the Gi/ o family - source_id: PMID:19478075 statement: Presynaptic M2/M4 autoreceptors restrain ACh release, and the restraint is pertussis-toxin (Gi/o) sensitive. supporting_text: This reduction was fully corrected by pertussis toxin, atropine (a nonselective muscarinic antagonist), or methoctramine (a selective M2/M4 muscarinic receptor antagonist). gocam_associations: - model: gomodel:67f85f2b00003584 activity: gomodel:67f85f2b00003584/67f85f2b00003585 title: CHRM2-mediated signaling via G-alpha-o (inhibitory), inhibiting adenylate cyclase following activation by acetylcholine (Human). description: CHRM2 G protein-coupled acetylcholine receptor activity (GO:0016907) upstream of GNAO1 and ADCY6 inhibition. The cached GNAO1-to-ADCY6 inhibitory edge has no attached edge evidence and is not used here to establish direct Go inhibition of ADCY6. - order: 2 role: Gi alpha switches node: id: g_alpha_i_o label: Gi alpha switches module_type: REGULATORY_STEP description: GTP-bound Gi alpha subunits mediate inhibitory effector signaling. This node represents GNAI1/GNAI2; M2-Go coupling is modeled separately and does not inherit a universal direct ADCY6 inhibition claim. Exact member alternatives enforce the selected receptor/G-protein subset; attached PANTHER descriptors record classification only. variant_sets: - id: g_alpha_i_o_member_choices label: Named member alternatives axis: gene product selection: ONE_OR_MORE variants: - id: g_alpha_i_o_gnai1_implementation label: GNAI1 annotons: - id: g_alpha_i_o_gnai1 label: GNAI1 — Gi alpha switches participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAI1 term: id: UniProtKB:P63096 label: Guanine nucleotide-binding protein G(i) subunit alpha-1 family: preferred_term: GNAI1 lineage term: id: PANTHER:PTHR10218:SF359 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(I) SUBUNIT ALPHA-1 representative_members: - preferred_term: GNAI1 term: id: UniProtKB:P63096 label: Guanine nucleotide-binding protein G(i) subunit alpha-1 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/GNAI1/GNAI1-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007197 label: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: GTP-bound Gi alpha subunits mediate inhibitory effector signaling. This node represents GNAI1/GNAI2; M2-Go coupling is modeled separately and does not inherit a universal direct ADCY6 inhibition claim. evidence: - source_id: PMID:11181437 statement: GTPgammaS assays in cells expressing human muscarinic receptors distinguish Gi and Gq/11 activation; this readout is not itself a direct assay of each adenylyl cyclase isoform. - source_id: PMID:7961880 statement: Transfected Gi2 mutants and M4 coupling affect a cAMP-dependent reporter; protein lipidation and assay context constrain interpretation. - id: g_alpha_i_o_gnai2_implementation label: GNAI2 annotons: - id: g_alpha_i_o_gnai2 label: GNAI2 — Gi alpha switches participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAI2 term: id: UniProtKB:P04899 label: Guanine nucleotide-binding protein G(i) subunit alpha-2 family: preferred_term: GNAI2 lineage term: id: PANTHER:PTHR10218:SF73 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(I) SUBUNIT ALPHA-2 representative_members: - preferred_term: GNAI2 term: id: UniProtKB:P04899 label: Guanine nucleotide-binding protein G(i) subunit alpha-2 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/GNAI2/GNAI2-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007197 label: adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: GTP-bound Gi alpha subunits mediate inhibitory effector signaling. This node represents GNAI1/GNAI2; M2-Go coupling is modeled separately and does not inherit a universal direct ADCY6 inhibition claim. evidence: - source_id: PMID:11181437 statement: GTPgammaS assays in cells expressing human muscarinic receptors distinguish Gi and Gq/11 activation; this readout is not itself a direct assay of each adenylyl cyclase isoform. - source_id: PMID:7961880 statement: Transfected Gi2 mutants and M4 coupling affect a cAMP-dependent reporter; protein lipidation and assay context constrain interpretation. - order: 2 optional: true role: inhibited adenylyl cyclase step node: id: machr_gi_adenylyl_cyclase label: Adenylyl cyclase effector interface description: The shared adenylyl cyclase interface represents the inhibitory cAMP branch downstream of Gi. It is optional because it is a regulated effector. The cached CHRM2/Go GO-CAM names ADCY6, but its inhibitory edge has no attached evidence and is not used here to establish a purified direct Go-ADCY6 interaction. module_ref: gpcr_camp_pka_signaling#adenylyl_cyclase_activation connections: - source: machr_gi_activation target: machr_gi_adenylyl_cyclase connection_type: NEGATIVELY_REGULATES description: Gi-mediated muscarinic signaling can reduce adenylyl cyclase/cAMP output; isoform and cellular context constrain the effect. This edge is not assigned to the separately modeled Go structural-coupling branch. evidence: - source_id: PMID:7961880 statement: M4 receptor/G-protein manipulations alter forskolin-driven cAMP-reporter output in JEG-3 cells; this is cellular signaling evidence, not isolated isoform-specific enzyme reconstitution. - source_id: PMID:17065363 statement: Human M2 in CHO cells inhibits forskolin-stimulated cAMP synthesis while also recruiting Gs/Gq at other agonist conditions; preferred inhibitory coupling is not exclusive. - id: machr_go_branch label: M2-Go reception module_type: SIGNALING_PATHWAY context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: A receptor/G-protein reception alternative. Downstream ion-channel and cAMP mechanisms are not inferred from the structural complex alone. annotons: - id: m2_go_receptor label: M2 receptor coupled to Go participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM2 term: id: UniProtKB:P08172 label: Muscarinic acetylcholine receptor M2 family: preferred_term: CHRM2 lineage term: id: PANTHER:PTHR24247:SF207 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M2 representative_members: - preferred_term: CHRM2 term: id: UniProtKB:P08172 label: Muscarinic acetylcholine receptor M2 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/CHRM2/CHRM2-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007213 label: G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human M2 receptor activation of Go; the structural preparation includes engineered receptor and stabilizing antibody components. evidence: - source_id: PMID:31073061 statement: The M2-GoA complex resolves a human receptor/G-alpha pair without requiring a downstream adenylyl cyclase assertion. - id: m2_go_switch label: Go alpha downstream of M2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAO1 term: id: UniProtKB:P09471 label: Guanine nucleotide-binding protein G(o) subunit alpha family: preferred_term: GNAO1 lineage term: id: PANTHER:PTHR10218:SF361 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(O) SUBUNIT ALPHA representative_members: - preferred_term: GNAO1 term: id: UniProtKB:P09471 label: Guanine nucleotide-binding protein G(o) subunit alpha description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/GNAO1/GNAO1-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007213 label: G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Human GNAO1 forms the M2-GoA complex (PDB 6OIK entity 2 maps to P09471). The structure establishes receptor coupling, not direct Go-ADCY6 inhibition. Cellular M4-Go cAMP-reporter effects are compatible with additional context-dependent signaling. evidence: - source_id: PMID:31073061 statement: M2-GoA structural coupling is directly resolved; RCSB 6OIK identifies the Go entity as human P09471, while the mouse component is the antibody fragment. - source_id: PMID:7961880 statement: Wild-type Go can support M4-dependent reduction of a cAMP reporter in transfected cells; this prevents a blanket Go/cAMP exclusion without establishing a direct ADCY6 mechanism. - source_id: file:modules/acetylcholine_signaling-source-analysis/README.md statement: Retained RCSB entity metadata distinguish engineered human GoA from the mouse antibody component and document the human Gi1/G11 chimera in the M1 preparation. gocam_associations: - model: gomodel:67f85f2b00003584 activity: gomodel:67f85f2b00003584/67f85f2b00003587 description: Cached GNAO1 activity downstream of CHRM2. Its ADCY6 inhibitory edge lacks edge-specific evidence; receptor coupling and downstream effector proof are assessed separately. connections: - source: m2_go_receptor target: m2_go_switch connection_type: POSITIVELY_REGULATES description: Activated M2 couples to the Go nucleotide switch. evidence: - source_id: PMID:31073061 statement: Receptor-bound GoA structure directly supports this coupling; exact construct metadata are retained in the source analysis. - id: machr_g14_branch label: M1/M3-G14 experimental coupling module_type: SIGNALING_PATHWAY description: A context-dependent reception alternative grounded in direct BRET measurements. Human construct provenance is inferred from the method/supplier chain; no direct PLC-beta activation or universal native M1/M3-G14 pathway follows from this experiment. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens annotons: - id: g_alpha_14_context label: G14 activation in the M1/M3 BRET system participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNA14 term: id: UniProtKB:O95837 label: Guanine nucleotide-binding protein subunit alpha-14 family: preferred_term: GNA14 exemplar within the G-alpha family representative_members: - preferred_term: GNA14 term: id: UniProtKB:O95837 label: Guanine nucleotide-binding protein subunit alpha-14 term: id: PANTHER:PTHR10218:SF213 label: GUANINE NUCLEOTIDE-BINDING PROTEIN SUBUNIT ALPHA-14 description: The listed representatives define this functional subset of a broader evolutionary family. Its official family name does not imply that every family member has the particular receptor or effector specificity asserted here. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007213 label: G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: G14 activation is measured by BRET. The human construct assignment is traced through the cited BRET platform and supplier catalog; the 2024 report does not supply an accession or sequence, so identity to the canonical O95837 sequence is not independently verified. evidence: - source_id: PMID:38671143 statement: Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay. - source_id: file:human/GNA14/GNA14-source-analysis/README.md statement: Reproducible method/supplier provenance supports a human-construct inference while explicitly leaving actual assayed-sequence identity unresolved. connections: - source: m1_m3_g14_receptor target: g_alpha_14_context connection_type: POSITIVELY_REGULATES description: Carbachol-bound M1/M3 activates G14 in the reported BRET expression system. evidence: - source_id: PMID:38671143 statement: Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay. parts: - order: 1 role: M1/M3 coupling to G14 in an expression assay node: id: m1_m3_g14_receptor label: M1/M3 coupling to G14 in an expression assay module_type: REGULATORY_STEP description: Carbachol activates G14 through M1/M3 in BRET experiments; ligand-dependent response magnitude and kinetics preclude universal coupling efficiency. Exact member alternatives enforce the selected receptor/G-protein subset; attached PANTHER descriptors record classification only. variant_sets: - id: m1_m3_g14_receptor_member_choices label: Named member alternatives axis: gene product selection: ONE_OR_MORE variants: - id: m1_m3_g14_receptor_chrm1_implementation label: CHRM1 annotons: - id: m1_m3_g14_receptor_chrm1 label: CHRM1 — M1/M3 coupling to G14 in an expression assay participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM1 (M1) term: id: UniProtKB:P11229 label: Muscarinic acetylcholine receptor M1 family: preferred_term: CHRM1 lineage term: id: PANTHER:PTHR24247:SF182 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M1 representative_members: - preferred_term: CHRM1 (M1) term: id: UniProtKB:P11229 label: Muscarinic acetylcholine receptor M1 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM1/CHRM1-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007213 label: G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Carbachol activates G14 through M1/M3 in BRET experiments; ligand-dependent response magnitude and kinetics preclude universal coupling efficiency. evidence: - source_id: PMID:38671143 statement: Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay. - id: m1_m3_g14_receptor_chrm3_implementation label: CHRM3 annotons: - id: m1_m3_g14_receptor_chrm3 label: CHRM3 — M1/M3 coupling to G14 in an expression assay participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRM3 (M3) term: id: UniProtKB:P20309 label: Muscarinic acetylcholine receptor M3 family: preferred_term: CHRM3 lineage term: id: PANTHER:PTHR24247:SF183 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M3 representative_members: - preferred_term: CHRM3 (M3) term: id: UniProtKB:P20309 label: Muscarinic acetylcholine receptor M3 description: Classification of the exact selected member; it does not allow substitution by another family member. evidence: - source_id: file:human/CHRM3/CHRM3-uniprot.txt statement: Normally fetched curated PANTHER classification of the selected accession. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity processes: - preferred_term: G protein-coupled acetylcholine receptor signaling pathway term: id: GO:0007213 label: G protein-coupled acetylcholine receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Carbachol activates G14 through M1/M3 in BRET experiments; ligand-dependent response magnitude and kinetics preclude universal coupling efficiency. evidence: - source_id: PMID:38671143 statement: Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - order: 6 role: acetylcholine hydrolysis and signal termination node: id: ach_hydrolysis label: AChE hydrolysis of acetylcholine in the synaptic cleft module_type: REACTION description: ACHE, anchored in the synaptic basal lamina at the neuromuscular junction and on membranes at central synapses, hydrolyses ACh to choline and acetate and so ends receptor activation. annotons: - id: ache_hydrolysis label: ACHE acetylcholinesterase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACHE term: id: UniProtKB:P22303 label: Acetylcholinesterase family: preferred_term: ACHE lineage term: id: PANTHER:PTHR43918:SF11 label: ACETYLCHOLINESTERASE representative_members: - preferred_term: ACHE term: id: UniProtKB:P22303 label: Acetylcholinesterase description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/ACHE/ACHE-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: acetylcholinesterase activity term: id: GO:0003990 label: acetylcholinesterase activity substrates: - preferred_term: acetylcholine term: id: CHEBI:15355 label: acetylcholine products: - preferred_term: choline term: id: CHEBI:15354 label: choline processes: - preferred_term: acetylcholine catabolic process in synaptic cleft term: id: GO:0001507 label: acetylcholine catabolic process in synaptic cleft locations: - preferred_term: synaptic cleft term: id: GO:0043083 label: synaptic cleft role_description: Terminates both nicotinic and muscarinic signalling and returns choline for reuptake; it is the target of organophosphates and of therapeutic cholinesterase inhibitors. evidence: - source_id: PMID:10869390 statement: AChE terminates transmission at cholinergic synapses. supporting_text: Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses - source_id: PMID:10869390 statement: AChE-null mice survive with delayed development, showing partial compensation by butyrylcholinesterase. supporting_text: These findings indicate that butyrylcholinesterase and possibly other enzymes are capable of compensating for some functions of AChE gocam_associations: - model: gomodel:6870555700001150 activity: gomodel:6870555700001150/689e7a5d00000955 title: Perlecan interaction with post-translationally modified dystroglycan is required for acetylcholinesterase localization and accumulation at the neuromuscular junction(Human) description: ACHE acetylcholinesterase activity (GO:0003990) part of acetylcholine catabolic process in synaptic cleft (GO:0001507); the model's main subject is ColQ/perlecan anchoring of AChE at the NMJ. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens - order: 7 optional: true role: muscarinic receptor desensitisation and G protein deactivation node: id: ach_muscarinic_termination label: GRK desensitisation of mAChRs and RGS acceleration of G alpha GTP hydrolysis module_type: REGULATORY_STEP description: GRK-mediated receptor phosphorylation/desensitization and RGS-accelerated G-alpha inactivation are distinct, context-dependent regulation mechanisms. RGS4 is separate from the RGS6-GNB5 heterodimer. These optional regulators affect signal duration and need not all act at a given synapse. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens variant_sets: - id: muscarinic_regulator_choices label: Context-dependent regulatory mechanisms axis: regulator mechanism selection: ONE_OR_MORE variants: - id: grk2_machr_regulatory_mechanism label: GRK2 phosphorylation of muscarinic receptors annotons: - id: grk2_machr label: GRK2 phosphorylation of muscarinic receptors participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK2 (beta-ARK1, Adrbk1) term: id: UniProtKB:P25098 label: G protein-coupled receptor kinase 2 family: preferred_term: GRK2 (beta-ARK1, Adrbk1) lineage term: id: PANTHER:PTHR24355:SF22 label: BETA-ADRENERGIC RECEPTOR KINASE 1 representative_members: - preferred_term: GRK2 (beta-ARK1, Adrbk1) term: id: UniProtKB:P25098 label: G protein-coupled receptor kinase 2 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/GRK2/GRK2-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity targets: - preferred_term: CHRM2 term: id: UniProtKB:P08172 label: Muscarinic acetylcholine receptor M2 processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway role_description: GRK2 phosphorylates M2 in purified biochemical experiments, with charged-phospholipid dependence. Human M2 is explicit in PMID:8798423, while kinase species is not established from its abstract. Human M2-M5 sequestration in COS-7 cells is a separate endpoint; the M1-negative sequestration result does not establish absence of M1 phosphorylation. evidence: - source_id: PMID:8798423 statement: Purified human M2 is phosphorylated by GRK2 in an agonist- and charged-phospholipid-dependent preparation. The abstract does not specify the kinase species. supporting_text: charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2. - source_id: PMID:9495886 statement: GRK2 coexpression facilitates sequestration of human M2-M5 in COS-7 cells; no significant effect on M1 sequestration is seen in this assay. This does not directly assay each receptor phosphorylation pair. supporting_text: These results indicate that the effect of GRK2 to facilitate receptor sequestration is not restricted to m2 receptors but is generalized to other muscarinic receptors except m1 receptors gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004469 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: GRK2 G protein-coupled receptor kinase activity (GO:0004703) in a desensitisation model for a different receptor (C5AR1); same gene and function, not an ACh model. - id: grk5_autoreceptor_regulatory_mechanism label: GRK5 M2 phosphorylation and muscarinic desensitization annotons: - id: grk5_autoreceptor label: GRK5 M2 phosphorylation and muscarinic desensitization participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK5 term: id: UniProtKB:P34947 label: G protein-coupled receptor kinase 5 family: preferred_term: GRK5 lineage term: id: PANTHER:PTHR24355:SF27 label: G PROTEIN-COUPLED RECEPTOR KINASE 5 representative_members: - preferred_term: GRK5 term: id: UniProtKB:P34947 label: G protein-coupled receptor kinase 5 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/GRK5/GRK5-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity targets: - preferred_term: CHRM2 term: id: UniProtKB:P08172 label: Muscarinic acetylcholine receptor M2 processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway locations: - preferred_term: presynapse term: id: GO:0098793 label: presynapse role_description: Purified GRK5 phosphorylates M2, while human M2 sequestration depends on the expression host. Mouse hippocampal GRK5 loss impairs M2/M4 internalization and inhibitory autoreceptor desensitization. Human presynaptic regulation is a homologous inference; the native mouse endpoint does not establish direct phosphorylation of human M4. evidence: - source_id: PMID:8288567 statement: Purified Sf9-expressed GRK5 phosphorylates M2 in an agonist-dependent manner. The abstract does not identify the kinase/receptor species; this establishes the subtype mechanism with a construct-provenance limit. supporting_text: GRK5 phosphorylates the beta 2-adrenergic receptor (beta 2AR), m2 muscarinic cholinergic receptor, and rhodopsin in an agonist-dependent manner - source_id: PMID:19478075 statement: GRK5 loss selectively impairs M2/M4 (not M1) internalisation and reduces ACh release. supporting_text: these results suggest that GRK5 deficiency leads to a reduced hippocampal ACh release and cholinergic hypofunction by selective impairment of desensitization of presynaptic M2/M4 autoreceptors. - source_id: PMID:9495886 statement: GRK5 facilitates sequestration of M2 but not M3 receptors. supporting_text: coexpression of GRK4 delta, GRK5, but not GRK6, in BHK-21 cells facilitated sequestration of m2, but not m3, receptors. - id: rgs2_gq_gap_regulatory_mechanism label: RGS2 GTPase-activating activity on G alpha q annotons: - id: rgs2_gq_gap label: RGS2 GTPase-activating activity on G alpha q participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS2 term: id: UniProtKB:P41220 label: Regulator of G protein signaling 2 family: preferred_term: RGS2 lineage term: id: PANTHER:PTHR10845:SF43 label: REGULATOR OF G-PROTEIN SIGNALING 2 representative_members: - preferred_term: RGS2 term: id: UniProtKB:P41220 label: Regulator of G protein signaling 2 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/RGS2/RGS2-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha role_description: 'Terminates the Gq branch (RGD: Rgs2 on the Gq proteins downstream of M3).' evidence: - source_id: PMID:19478087 statement: RGS2 is a potent and selective GAP for G alpha q. supporting_text: RGS2 is unique in its in vitro potency and selectivity as a GAP for Galpha(q) subunits. - id: rgs4_gi_gap_regulatory_mechanism label: RGS4 GAP activity on Gi annotons: - id: rgs4_gi_gap label: RGS4 GAP activity on Gi participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS4 term: id: UniProtKB:P49798 label: Regulator of G protein signaling 4 family: preferred_term: RGS4 lineage term: id: PANTHER:PTHR10845:SF184 label: REGULATOR OF G-PROTEIN SIGNALING 4 representative_members: - preferred_term: RGS4 term: id: UniProtKB:P49798 label: Regulator of G protein signaling 4 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/RGS4/RGS4-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: GNAI1 term: id: UniProtKB:P63096 label: Guanine nucleotide-binding protein G(i) subunit alpha-1 role_description: RGS4 accelerates Gi-family GTP hydrolysis. Native cardiac effects are not assumed interchangeable with the RGS6-Gbeta5 complex. evidence: - source_id: PMID:8756726 statement: RGS4 accelerates GTP hydrolysis by Gi alpha subunits. supporting_text: We have found that two RGS family members, GAIP and RGS4, are GTPase-activating proteins (GAPs), accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold. - source_id: PMID:8756726 statement: Gs alpha is not a substrate, giving Gi-family selectivity. supporting_text: All Gi subfamily members assayed were substrates for these GAPs; Gs alpha was not. - id: human_rgs6_gnb5_gap_regulatory_mechanism label: RGS6–GNB5 GAP complex annotons: - id: human_rgs6_gnb5_gap label: RGS6–GNB5 GAP complex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: RGS6–GNB5 complex active_units: - id: human_rgs6_gnb5_gap_rgs label: RGS6 catalytic GAP component participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RGS6 term: id: UniProtKB:P49758 label: Regulator of G protein signaling 6 family: preferred_term: RGS6 lineage term: id: PANTHER:PTHR45746:SF2 label: REGULATOR OF G-PROTEIN SIGNALING 6 representative_members: - preferred_term: RGS6 term: id: UniProtKB:P49758 label: Regulator of G protein signaling 6 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/RGS6/RGS6-uniprot.txt statement: Curated PANTHER classification of this exact member. role: RGS domain accelerates G-alpha GTP hydrolysis; it does not hydrolyze GTP as its own substrate. - id: human_rgs6_gnb5_gap_beta5 label: GNB5 partner participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNB5 term: id: UniProtKB:O14775 label: Guanine nucleotide-binding protein subunit beta-5 family: preferred_term: GNB5 lineage term: id: PANTHER:PTHR19850 label: GUANINE NUCLEOTIDE-BINDING PROTEIN BETA G PROTEIN BETA representative_members: - preferred_term: GNB5 term: id: UniProtKB:O14775 label: Guanine nucleotide-binding protein subunit beta-5 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:human/GNB5/GNB5-uniprot.txt statement: Curated PANTHER classification of this exact member. role: GGL-binding partner required for stable native R7 complex expression and function in the sampled cardiac context. term: id: GO:1902773 label: GTPase activator complex function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity role_description: RGS6-family GAP activity is represented on the heterodimer. Purified-complex experiments establish Go-directed GAP activity; the native cardiac response does not identify every individual G-alpha substrate. GNB5 is not itself a GTPase. evidence: - source_id: PMID:10521509 statement: Purified RGS6/Gbeta5 complexes accelerate Go GTP hydrolysis; their biochemical target is not inferred from RGS4. - source_id: PMID:20884879 statement: Native mouse loss of either partner prolongs muscarinic potassium-current deactivation; partner association supports Rgs6 expression/stability. notes: Human exemplars are homologous components of the biochemically defined complex; the cardiac kinetics evidence below is explicitly from mouse and is not a direct human cardiomyocyte assay. notes: Any supported regulator mechanism can occur without all the others. The RGS6-GNB5 heterodimer remains one indivisible complex alternative; its active_units specify both partners. - order: 8 optional: true role: comparative hair-cell receptor capacity node: id: rat_hair_cell_receptor label: Rat alpha9/alpha10 receptor comparator module_type: PROTEIN_COMPLEX description: Rat alpha9/alpha10 channels have substantially higher calcium permeability than the chicken receptor in matched expression assays. Native hair-cell responses involve potassium channels and calcium handling beyond this receptor segment. annotons: - id: rat_hair_cell_receptor_channel label: Rat alpha9/alpha10 receptor comparator cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Rat alpha9/alpha10 receptor comparator term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: rat_hair_cell_receptor_chrna9 label: Chrna9 subunit role: ACh-binding subunit; can form homomers in heterologous expression. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Chrna9 term: id: UniProtKB:P43144 label: Neuronal acetylcholine receptor subunit alpha-9 family: preferred_term: Chrna9 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: Chrna9 term: id: UniProtKB:P43144 label: Neuronal acetylcholine receptor subunit alpha-9 description: Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted. evidence: - source_id: file:rat/Chrna9/Chrna9-uniprot.txt statement: Curated classification of this exemplar in the ligand-gated ion channel family. - id: rat_hair_cell_receptor_chrna10 label: Chrna10 subunit role: Partner subunit required for the native heteromer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Chrna10 term: id: UniProtKB:Q9JLB5 label: Neuronal acetylcholine receptor subunit alpha-10 family: preferred_term: Chrna10 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: Chrna10 term: id: UniProtKB:Q9JLB5 label: Neuronal acetylcholine receptor subunit alpha-10 description: Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted. evidence: - source_id: file:rat/Chrna10/Chrna10-uniprot.txt statement: Curated classification of this exemplar in the ligand-gated ion channel family. function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: acetylcholine receptor signaling pathway term: id: GO:0095500 label: acetylcholine receptor signaling pathway role_description: Rat alpha9/alpha10 channels have substantially higher calcium permeability than the chicken receptor in matched expression assays. Native hair-cell responses involve potassium channels and calcium handling beyond this receptor segment. Current gene accessions identify the sampled orthologs; historical assay constructs are not assumed identical without supplementary sequence mapping. evidence: - source_id: PMID:22371598 statement: Rat alpha9/alpha10 channels have substantially higher calcium permeability than the chicken receptor in matched expression assays. Native hair-cell responses involve potassium channels and calcium handling beyond this receptor segment. supporting_text: recombinant and native chicken α9α10 receptors - source_id: PMID:34867208 statement: Review interprets the taxon-dependent channel properties and distinction between calcium entry and net hair-cell inhibition. context: taxa: - preferred_term: Rattus norvegicus term: id: NCBITaxon:10116 label: Rattus norvegicus - order: 9 optional: true role: comparative hair-cell receptor capacity node: id: chicken_hair_cell_receptor label: Chicken alpha9/alpha10 receptor comparator module_type: PROTEIN_COMPLEX description: Chicken alpha9/alpha10 channels have lower calcium permeability than rat channels; native basilar-papilla recordings corroborate the difference. Calcium-store contributions differ under the tested conditions, so equal receptor names do not imply identical downstream coupling. annotons: - id: chicken_hair_cell_receptor_channel label: Chicken alpha9/alpha10 receptor comparator cation-channel activity participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Chicken alpha9/alpha10 receptor comparator term: id: GO:0005892 label: acetylcholine-gated channel complex active_units: - id: chicken_hair_cell_receptor_chrna9 label: CHRNA9 subunit role: ACh-binding subunit; can form homomers in heterologous expression. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA9 term: id: UniProtKB:Q9PTS8 label: Neuronal acetylcholine receptor subunit alpha-9 family: preferred_term: CHRNA9 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA9 term: id: UniProtKB:Q9PTS8 label: Neuronal acetylcholine receptor subunit alpha-9 description: Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted. evidence: - source_id: file:CHICK/CHRNA9/CHRNA9-uniprot.txt statement: Curated classification of this exemplar in the ligand-gated ion channel family. - id: chicken_hair_cell_receptor_chrna10 label: CHRNA10 subunit role: Partner subunit required for the native heteromer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHRNA10 term: id: UniProtKB:Q9I8C7 label: Neuronal acetylcholine receptor subunit alpha-10 family: preferred_term: CHRNA10 nicotinic receptor subunit lineage term: id: PANTHER:PTHR18945 label: NEUROTRANSMITTER GATED ION CHANNEL representative_members: - preferred_term: CHRNA10 term: id: UniProtKB:Q9I8C7 label: Neuronal acetylcholine receptor subunit alpha-10 description: Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted. evidence: - source_id: file:CHICK/CHRNA10/CHRNA10-uniprot.txt statement: Curated classification of this exemplar in the ligand-gated ion channel family. function: preferred_term: acetylcholine-gated monoatomic cation-selective channel activity term: id: GO:0022848 label: acetylcholine-gated monoatomic cation-selective channel activity processes: - preferred_term: acetylcholine receptor signaling pathway term: id: GO:0095500 label: acetylcholine receptor signaling pathway role_description: Chicken alpha9/alpha10 channels have lower calcium permeability than rat channels; native basilar-papilla recordings corroborate the difference. Calcium-store contributions differ under the tested conditions, so equal receptor names do not imply identical downstream coupling. Current gene accessions identify the sampled orthologs; historical assay constructs are not assumed identical without supplementary sequence mapping. evidence: - source_id: PMID:22371598 statement: Chicken alpha9/alpha10 channels have lower calcium permeability than rat channels; native basilar-papilla recordings corroborate the difference. Calcium-store contributions differ under the tested conditions, so equal receptor names do not imply identical downstream coupling. supporting_text: recombinant and native chicken α9α10 receptors - source_id: PMID:34867208 statement: Review interprets the taxon-dependent channel properties and distinction between calcium entry and net hair-cell inhibition. context: taxa: - preferred_term: Gallus gallus term: id: NCBITaxon:9031 label: Gallus gallus - order: 10 optional: true role: native mouse cardiac regulatory comparison node: id: mouse_cardiac_regulation label: Mouse Rgs6–Gnb5 regulation of cardiac M2 signaling module_type: REGULATORY_STEP context: taxa: - preferred_term: Mus musculus term: id: NCBITaxon:10090 label: Mus musculus description: Native mouse comparison separates the receptor and the obligatory Rgs6-Gnb5 regulatory complex. It samples signal termination rather than a complete mouse cholinergic transmission pathway. parts: - order: 1 role: M2-driven cardiac signaling node: id: mouse_m2_signal label: M2-initiated cardiac response annotons: - id: mouse_m2_receptor label: Mouse M2 muscarinic receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Chrm2 term: id: UniProtKB:Q9ERZ4 label: Muscarinic acetylcholine receptor M2 family: preferred_term: Chrm2 lineage term: id: PANTHER:PTHR24247:SF207 label: MUSCARINIC ACETYLCHOLINE RECEPTOR M2 representative_members: - preferred_term: Chrm2 term: id: UniProtKB:Q9ERZ4 label: Muscarinic acetylcholine receptor M2 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:mouse/Chrm2/Chrm2-uniprot.txt statement: Curated PANTHER classification of this exact member. function: preferred_term: G protein-coupled acetylcholine receptor activity term: id: GO:0016907 label: G protein-coupled acetylcholine receptor activity role_description: M2-driven signaling in native atrial and sinoatrial cells is the regulated context. GIRK is the measured downstream endpoint, outside this sampled receptor/regulator segment. evidence: - source_id: PMID:20884879 statement: Native mouse atrial and sinoatrial cells show carbachol-evoked muscarinic currents with prolonged deactivation after Rgs6 or Gnb5 loss. - order: 2 role: Rgs6-Gnb5 temporal regulation node: id: mouse_rgs6_regulation label: Rgs6-Gnb5 GAP complex annotons: - id: mouse_rgs6_gnb5_gap label: Rgs6–Gnb5 GAP complex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Rgs6–Gnb5 complex active_units: - id: mouse_rgs6_gnb5_gap_rgs label: Rgs6 catalytic GAP component participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Rgs6 term: id: UniProtKB:Q9Z2H2 label: Regulator of G protein signaling 6 family: preferred_term: Rgs6 lineage term: id: PANTHER:PTHR45746:SF2 label: REGULATOR OF G-PROTEIN SIGNALING 6 representative_members: - preferred_term: Rgs6 term: id: UniProtKB:Q9Z2H2 label: Regulator of G protein signaling 6 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:mouse/Rgs6/Rgs6-uniprot.txt statement: Curated PANTHER classification of this exact member. role: RGS domain accelerates G-alpha GTP hydrolysis; it does not hydrolyze GTP as its own substrate. - id: mouse_rgs6_gnb5_gap_beta5 label: Gnb5 partner participant: selector_type: GENE_PRODUCT gene_product: preferred_term: Gnb5 term: id: UniProtKB:P62881 label: Guanine nucleotide-binding protein subunit beta-5 family: preferred_term: Gnb5 lineage term: id: PANTHER:PTHR19850 label: GUANINE NUCLEOTIDE-BINDING PROTEIN BETA G PROTEIN BETA representative_members: - preferred_term: Gnb5 term: id: UniProtKB:P62881 label: Guanine nucleotide-binding protein subunit beta-5 description: Classification of this concrete exemplar; the surrounding activity remains limited to the named member and biological context. No ancestral node or universal family function is inferred. evidence: - source_id: file:mouse/Gnb5/Gnb5-uniprot.txt statement: Curated PANTHER classification of this exact member. role: GGL-binding partner required for stable native R7 complex expression and function in the sampled cardiac context. term: id: GO:1902773 label: GTPase activator complex function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity role_description: RGS6-family GAP activity is represented on the heterodimer. Purified-complex experiments establish Go-directed GAP activity; the native cardiac response does not identify every individual G-alpha substrate. GNB5 is not itself a GTPase. evidence: - source_id: PMID:10521509 statement: Purified RGS6/Gbeta5 complexes accelerate Go GTP hydrolysis; their biochemical target is not inferred from RGS4. - source_id: PMID:20884879 statement: Native mouse loss of either partner prolongs muscarinic potassium-current deactivation; partner association supports Rgs6 expression/stability. connections: - source: mouse_rgs6_regulation target: mouse_m2_signal connection_type: NEGATIVELY_REGULATES description: The Rgs6-Gnb5 complex accelerates termination of the downstream muscarinic potassium-current response. This is not a claim of direct receptor phosphorylation or ligand-binding inhibition. evidence: - source_id: PMID:20884879 statement: Deletion of either partner prolongs deactivation in native mouse atrial cells; the Rgs6 phenotype also occurs in sinoatrial cells. - source_id: PMID:24318880 statement: Native mouse comparison finds enhanced parasympathetic influence after RGS6 ablation, not RGS4 ablation. supporting_text: RGS6 ablation enhances parasympathetic influence on the heart; RGS4 ablation does not. connections: - source: ach_choline_uptake target: ach_synthesis connection_type: PROVIDES_INPUT_FOR description: Transported choline is the substrate acetylated by CHAT. This links independently demonstrated transport and catalytic reactions, without asserting a transporter-enzyme complex. evidence: - source_id: PMID:11027560 statement: Human transporter expression establishes choline uptake. - source_id: PMID:17144655 statement: Human CHAT structures define choline and acetyl-CoA recognition and the acetyl-transfer mechanism. - source: ach_synthesis target: ach_vesicle_loading connection_type: PROVIDES_INPUT_FOR description: CHAT-generated cytosolic acetylcholine is available as substrate for VAChT loading; chemical continuity is inferred from the independently measured reactions. evidence: - source_id: PMID:17144655 statement: CHAT produces acetylcholine from choline and acetyl-CoA. - source_id: PMID:8910293 statement: Human VAChT expressed in PC-12 cells mediates ATP/proton-gradient-dependent vesicular acetylcholine uptake. - source: ach_vesicle_loading target: ach_release connection_type: PROVIDES_INPUT_FOR description: Vesicular acetylcholine supplies the transmitter cargo for exocytosis. Loading and fusion are distinct mechanisms; the conserved fusion interface has comparative cholinergic evidence rather than an all-human reconstitution. evidence: - source_id: PMID:8910293 statement: Human VAChT confers vesicular acetylcholine accumulation in a rat cell line. - source_id: PMID:10526333 statement: C. elegans unc-13 loss nearly abolishes evoked cholinergic release despite morphologically docked vesicles, supporting the generic priming/fusion interface; it is not a human protein assay. - source: ach_release target: ach_reception connection_type: PROVIDES_INPUT_FOR description: Extracellular acetylcholine activates the receptor implementations. Native release and recombinant human receptor responses provide complementary evidence, rather than a single reconstructed human synapse. evidence: - source_id: PMID:10526333 statement: Native worm neuromuscular electrophysiology connects evoked vesicular release to cholinergic postsynaptic responses. - source_id: PMID:8788941 statement: Recombinant human adult and fetal muscle receptor assemblies respond to acetylcholine. - source_id: PMID:11181437 statement: Agonist-stimulated human muscarinic receptors expressed in CHO cells activate G proteins with subtype- and agonist-dependent profiles. - source: ach_release target: ach_hydrolysis connection_type: PROVIDES_INPUT_FOR description: Released acetylcholine is an extracellular substrate for acetylcholinesterase; this is a chemical substrate relation. evidence: - source_id: PMID:1517212 statement: Human acetylcholinesterase catalytic-triad substitutions abolish enzymatic activity while preserving secretion and folding. - source_id: file:human/ACHE/ACHE-uniprot.txt statement: Publication-linked curated reaction specifies acetylcholine hydrolysis to choline and acetate. supporting_text: acetylcholine + H2O = choline + acetate + H(+) - source: ach_hydrolysis target: ach_reception connection_type: NEGATIVELY_REGULATES description: Hydrolysis lowers available agonist and thereby limits continuing receptor activation. Acetylcholinesterase is the principal terminator in this context; partial compensation in knockout mice prevents an absolute requirement claim. evidence: - source_id: PMID:10869390 statement: AChE-null mice survive with substantial physiological abnormalities and compensatory hydrolysis; the study supports a principal, not exclusive, termination role. - source_id: PMID:1517212 statement: Human mutagenesis independently establishes the catalytic activity underlying agonist removal. - source: ach_hydrolysis target: ach_choline_uptake connection_type: PROVIDES_INPUT_FOR description: Choline released by acetylcholine hydrolysis can enter the extracellular pool used by CHT1. This chemical recycling relation does not require direct binding between ACHE and SLC5A7. evidence: - source_id: file:human/ACHE/ACHE-uniprot.txt statement: Curated catalytic reaction produces choline. supporting_text: acetylcholine + H2O = choline + acetate + H(+) - source_id: PMID:11027560 statement: Human CHT1 transports extracellular choline with high affinity. - source: machr_gi_activation target: ach_release connection_type: NEGATIVELY_REGULATES description: Presynaptic M2/M4-dependent inhibitory feedback limits further acetylcholine release. The native experimental support is mouse hippocampus and a cholinergic cell line; placement in the human module is a qualified homologous physiological inference. evidence: - source_id: PMID:19478075 statement: Reduced evoked release after mouse GRK5 loss is corrected by an M2/M4 antagonist; cell-line release is also restored by pertussis toxin or muscarinic antagonists. This is pathway-level inhibition, not direct binding of G-alpha to a vesicle-fusion protein. - source: ach_muscarinic_termination target: muscarinic_reception connection_type: NEGATIVELY_REGULATES description: Optional GRK-associated desensitization and RGS-accelerated G-alpha inactivation shorten muscarinic responses in their respective contexts. RGS proteins act on G proteins rather than directly phosphorylating receptors. evidence: - source_id: PMID:9495886 statement: Coexpression experiments measure receptor sequestration with subtype and cell-line dependence. - source_id: PMID:8756726 statement: RGS4 accelerates Gi-family GTP hydrolysis. - source_id: PMID:19478087 statement: Wild-type RGS2 has potent Gq-directed GAP activity. - source_id: PMID:20884879 statement: Native mouse Rgs6-Gnb5 controls deactivation kinetics of the M2-driven cardiac response. - source: grk5_autoreceptor target: machr_gi_activation connection_type: NEGATIVELY_REGULATES description: GRK5-associated muscarinic desensitization limits inhibitory autoreceptor feedback. Native M2/M4 presynaptic evidence is from mouse; human receptor-expression evidence establishes context-dependent M2 sequestration, without measuring direct phosphorylation of every subtype. evidence: - source_id: PMID:19478075 statement: Mouse hippocampal slices lacking GRK5 show reduced M2/M4 internalization and stronger inhibitory feedback on acetylcholine release. - source_id: PMID:9495886 statement: GRK5 coexpression facilitates human M2 sequestration in BHK-21 cells; this is not a universal effect across receptor subtypes or host cells. knowledge_gaps: - gap_statement: Which GRK and RGS proteins act on each muscarinic subtype in native neurons and effector tissues, and with what selectivity, is not known. The assignments drawn by RGD come largely from overexpression or single-tissue knockout work. boundary: It is established that GRK2 overexpression promotes sequestration of M2 to M5 but not M1 receptors, that GRK5 loss selectively impairs M2/M4 autoreceptor internalisation and lowers hippocampal ACh release, that RGS2 is a selective GAP for G alpha q and that RGS4 is a GAP for G alpha i. status: OPEN gap_kind: - BIOLOGY significance: Without subtype-resolved assignments the termination part of this module cannot be weighted, and subtype-selective muscarinic drugs cannot be matched to the desensitisation machinery that will shape their effect. provenance: - reference_id: PMID:9495886 supporting_text: GRK4 delta, GRK5 and GRK6 did not facilitate sequestration of m1-m5 receptors in COS-7 cells, except that the sequestration of m2 receptors tended to be facilitated by coexpression of GRK4 delta, GRK5 and GRK6. - gap_statement: The native subunit composition and stoichiometry of neuronal nicotinic receptors in most cell types is unresolved, including which alpha and beta combinations exist in vivo and how accessory subunits such as alpha5 and beta3 are distributed. boundary: Immunoprecipitation and knockout work establish alpha4beta2*, alpha6beta2* and alpha4alpha6beta2* receptors in dopaminergic terminal fields, and alpha3beta4* as the principal autonomic subtype, but the inventory is incomplete. status: OPEN gap_kind: - BIOLOGY significance: Subtype composition sets agonist sensitivity, calcium permeability and desensitisation, so it determines which receptors mediate nicotine reinforcement and which are tractable drug targets. provenance: - reference_id: PMID:12944511 supporting_text: However, DA neurons express mRNAs coding for most, if not all, neuronal nAChR subunits, and the subunit composition of functional nAChRs has been difficult to establish. references: - id: PMID:32272141 title: Progress in nicotinic receptor structural biology. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full cached text inspected for the stated finding. Structural review supports restricted pentamer assemblies and composition-dependent ligand interfaces; it does not license arbitrary neuronal subunit combinations. findings: - statement: Structural review supports restricted pentamer assemblies and composition-dependent ligand interfaces; it does not license arbitrary neuronal subunit combinations. supporting_text: assemble in limited combinations - id: PMID:34867208 title: 'The Hair Cell α9α10 Nicotinic Acetylcholine Receptor: Odd Cousin in an Old Family.' full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full cached text inspected for the stated finding. The hair-cell response combines alpha9/alpha10-mediated calcium entry with potassium-channel activation; net inhibition is distinct from receptor cation current. findings: - statement: The hair-cell response combines alpha9/alpha10-mediated calcium entry with potassium-channel activation; net inhibition is distinct from receptor cation current. supporting_text: secondary activation of a nearby calcium-dependent SK2 potassium channel - id: PMID:30700248 title: Evolution of vertebrate nicotinic acetylcholine receptors. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full cached text inspected for the stated finding. Phylogeny, synteny and intron comparisons reveal a broader vertebrate repertoire and mammalian losses, so the human subunit list is not a universal vertebrate inventory. findings: - statement: Phylogeny, synteny and intron comparisons reveal a broader vertebrate repertoire and mammalian losses, so the human subunit list is not a universal vertebrate inventory. supporting_text: Three of these have been lost in mammals - id: PMID:22371598 title: Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full cached text inspected for the stated finding. Rat and chicken alpha9/alpha10 receptors differ in calcium permeability, supported by recombinant measurements and native chicken recordings; equivalent pore labels do not imply equivalent physiology. findings: - statement: Rat and chicken alpha9/alpha10 receptors differ in calcium permeability, supported by recombinant measurements and native chicken recordings; equivalent pore labels do not imply equivalent physiology. supporting_text: recombinant and native chicken α9α10 receptors - id: PMID:8788941 title: Functional and non-functional isoforms of the human muscle acetylcholine receptor. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract inspected; claims are restricted to explicitly reported experiments/results. Human fetal and adult muscle channels are alternative pentamers, measured after expression in oocytes; canonical alpha1 and its alpha-plus splice form differ in functional assembly. findings: - statement: Human fetal and adult muscle channels are alternative pentamers, measured after expression in oocytes; canonical alpha1 and its alpha-plus splice form differ in functional assembly. supporting_text: adult (alpha 2 beta delta epsilon) and fetal (alpha 2 beta delta gamma) - id: PMID:8663494 title: Assembly of human neuronal nicotinic receptor alpha5 subunits with alpha3, beta2, and beta4 subunits. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract inspected; claims are restricted to explicitly reported experiments/results. Human alpha3/beta4 channels assemble with or without alpha5; the accessory subunit changes desensitization rather than constituting an obligatory component of all channels. findings: - statement: Human alpha3/beta4 channels assemble with or without alpha5; the accessory subunit changes desensitization rather than constituting an obligatory component of all channels. supporting_text: alpha5 subunits coassembled very efficiently with alpha3beta2 or alpha3beta4 combinations. - id: PMID:20923852 title: Expression of functional human α6β2β3* acetylcholine receptors in Xenopus laevis oocytes achieved through subunit chimeras and concatamers. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract inspected; claims are restricted to explicitly reported experiments/results. Human alpha6-containing receptor concatamers support defined functional assemblies; native unlinked receptor composition is a separate question. findings: - statement: Human alpha6-containing receptor concatamers support defined functional assemblies; native unlinked receptor composition is a separate question. supporting_text: Concatameric subunits permit assembly of functional α6β2β3* AChRs with defined subunit compositions and subunit orders. - id: PMID:27698419 title: X-ray structure of the human α4β2 nicotinic receptor. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full cached text inspected for the stated finding. Both human alpha4/beta2 stoichiometries are functional; the 2016 structure isolates the beta-rich form with engineered intracellular-domain deletions. findings: - statement: Both human alpha4/beta2 stoichiometries are functional; the 2016 structure isolates the beta-rich form with engineered intracellular-domain deletions. supporting_text: The α4β2 receptor is known to assemble in two functional subunit stoichiometries, 3α:2β and 2α:3β. - id: PMID:8906617 title: Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract inspected; claims are restricted to explicitly reported experiments/results. Human alpha2/beta2 and alpha7 receptor capacity is directly established by expression and ACh-evoked currents; exact native distributions and copy numbers are not established by those assays. findings: - statement: Human alpha2/beta2 and alpha7 receptor capacity is directly established by expression and ACh-evoked currents; exact native distributions and copy numbers are not established by those assays. supporting_text: confirming functional expression of human nicotinic receptors. - id: PMID:41461581 title: 'The Concise Guide to PHARMACOLOGY 2025/26: G protein-coupled receptors.' reference_review: relevance: HIGH correctness: VERIFIED review_notes: Muscarinic section of the full guide inspected. Coupling preference language limits the module generalization; this reference does not prove individual native GRK/RGS targets. findings: - statement: Muscarinic receptor classes preferentially couple to different G-protein families, with contextual variation. supporting_text: M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. - id: PMID:11752216 title: A novel human nicotinic receptor subunit, alpha10, that confers functionality to the alpha9-subunit. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract directly reports cloned human alpha9/alpha10 coexpression and ACh-evoked currents. Native coassembly is a stated inference, not a directly imaged native complex. findings: - statement: Human alpha10 coexpression produces robust alpha9-containing ACh-responsive channels; alpha10 alone is not a functional homomer. supporting_text: it promoted robust acetylcholine-evoked currents when coinjected with alpha9. - id: PMID:20881005 title: Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)₂α5 AChR function. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full methods identify human cDNAs, linked alpha4/beta2 tetramer plus alpha5 in oocytes, and stable human cell-line experiments. The exact tested composition is represented without assuming identical native receptor stoichiometry everywhere. findings: - statement: Defined human alpha4/beta2/alpha5 assemblies were functionally assayed; the accessory subunit is required for this alternative but not for alpha4/beta2-only channels. supporting_text: Oocytes were injected with 5 ng of the β2-α4-β2-α4 concatamer cRNA and 2.5 ng of α5 cRNA. - id: PMID:10521509 title: Regulators of G protein signaling 6 and 7. Purification of complexes with gbeta5 and assessment of their effects on g protein-mediated signaling pathways. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract-level result used with explicit assay/context limits. Purified RGS6-Gbeta5 and RGS7-Gbeta5 complexes are Go-directed GAPs; they are distinct from conventional beta-gamma complexes. findings: - statement: Purified RGS6-Gbeta5 and RGS7-Gbeta5 complexes are Go-directed GAPs; they are distinct from conventional beta-gamma complexes. supporting_text: act as GTPase-activating proteins specifically toward Galpha(o). - id: PMID:20884879 title: RGS6/Gβ5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full relevant experimental text inspected. Native mouse Rgs6 and Gnb5 loss prolongs cardiac muscarinic response deactivation; the partner is required for Rgs6 expression or stability. findings: - statement: Native mouse Rgs6 and Gnb5 loss prolongs cardiac muscarinic response deactivation; the partner is required for Rgs6 expression or stability. supporting_text: the physical association with Gβ5 is critical for the expression and/or stability of Rgs6 - id: PMID:24318880 title: RGS6, but not RGS4, is the dominant regulator of G protein signaling (RGS) modulator of the parasympathetic regulation of mouse heart rate. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full relevant experimental text inspected. Native cardiac comparisons distinguish RGS6 regulation from RGS4; neither a universal RGS replacement nor an exact G-alpha catalytic target follows. findings: - statement: Native cardiac comparisons distinguish RGS6 regulation from RGS4; neither a universal RGS replacement nor an exact G-alpha catalytic target follows. supporting_text: RGS6 ablation enhances parasympathetic influence on the heart; RGS4 ablation does not. - id: PMID:31073061 title: Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full relevant experimental text inspected. M1-G11 and M2-Go structural coupling is resolved; the former uses a Gi1/G11 chimera. The complexes do not directly establish every downstream effector mechanism. findings: - statement: M1-G11 and M2-Go structural coupling is resolved; the former uses a Gi1/G11 chimera. The complexes do not directly establish every downstream effector mechanism. - id: PMID:7961880 title: Regulation of cAMP-mediated gene transcription by wild type and mutated G-protein alpha subunits. Inhibition of adenylyl cyclase activity by muscarinic receptor-activated and constitutively activated G(o) alpha. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract-level result used with explicit assay/context limits. Wild-type Go supports M4-dependent reduction of a cAMP reporter in transfected JEG-3 cells; this is not purified Go-ADCY6 inhibition. findings: - statement: Wild-type Go supports M4-dependent reduction of a cAMP reporter in transfected JEG-3 cells; this is not purified Go-ADCY6 inhibition. supporting_text: Transfected wild type G(o) alpha was also able to couple the m4 mAChR receptor to inhibition of AC. - id: PMID:11027560 title: Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human CHT1 cloned from spinal cord confers high-affinity sodium/chloride-dependent choline uptake in COS-7 preparations; rate limitation is qualified to many physiological circumstances. findings: - statement: Human CHT1 cloned from spinal cord confers high-affinity sodium/chloride-dependent choline uptake in COS-7 preparations; rate limitation is qualified to many physiological circumstances. - id: PMID:17144655 title: Substrate binding and catalytic mechanism of human choline acetyltransferase. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human CHAT binary structures and catalytic analysis establish choline/acetyl-CoA substrate recognition and acetyl transfer. findings: - statement: Human CHAT binary structures and catalytic analysis establish choline/acetyl-CoA substrate recognition and acetyl transfer. - id: PMID:8910293 title: Active transport of acetylcholine by the human vesicular acetylcholine transporter. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human VAChT expressed in rat PC-12 cells mediates vesicular acetylcholine uptake dependent on ATP and the proton gradient; the expression host is not the protein species. findings: - statement: Human VAChT expressed in rat PC-12 cells mediates vesicular acetylcholine uptake dependent on ATP and the proton gradient; the expression host is not the protein species. - id: PMID:1517212 title: Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human ACHE catalytic-triad substitutions abolish activity without preventing folding or secretion, separating catalysis from protein production. findings: - statement: Human ACHE catalytic-triad substitutions abolish activity without preventing folding or secretion, separating catalysis from protein production. - id: PMID:10526333 title: UNC-13 is required for synaptic vesicle fusion in C. elegans. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Native C. elegans synaptic physiology links UNC-13 to priming/fusion of cholinergic and GABAergic vesicles. It supports the generic release interface, not a direct human construct result. findings: - statement: Native C. elegans synaptic physiology links UNC-13 to priming/fusion of cholinergic and GABAergic vesicles. It supports the generic release interface, not a direct human construct result. - id: PMID:8626481 title: Regulation of phospholipase C-beta1 by Gq and m1 muscarinic cholinergic receptor. Steady-state balance of receptor-mediated activation and GTPase-activating protein-promoted deactivation. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Purified M1/Gq/PLC-beta1 reconstitution establishes agonist/GTP-dependent PLC stimulation and PLC feedback GAP activity. Protein species are not established from the abstract. findings: - statement: Purified M1/Gq/PLC-beta1 reconstitution establishes agonist/GTP-dependent PLC stimulation and PLC feedback GAP activity. Protein species are not established from the abstract. supporting_text: Both GTP and agonist were required for PLC activation - id: PMID:38671143 title: Agonist-selective activation of individual G-proteins by muscarinic receptors. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Relevant full-text results inspected. Full-text BRET results show carbachol activation of G14 by M1/M3 with subtype-, ligand- and G-alpha-dependent kinetics. Human G14 provenance is traced through platform methods and supplier metadata; no sequence confirmation or direct PLC assay is claimed. findings: - statement: Full-text BRET results show carbachol activation of G14 by M1/M3 with subtype-, ligand- and G-alpha-dependent kinetics. Human G14 provenance is traced through platform methods and supplier metadata; no sequence confirmation or direct PLC assay is claimed. - id: PMID:9495886 title: 'Sequestration of human muscarinic acetylcholine receptor hm1-hm5 subtypes: effect of G protein-coupled receptor kinases GRK2, GRK4, GRK5 and GRK6.' full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human M1-M5 receptor sequestration in COS-7 and BHK-21 cells depends on receptor subtype, GRK and host. The endpoint is loss of surface ligand binding, not direct phosphorylation of every receptor. findings: - statement: Human M1-M5 receptor sequestration in COS-7 and BHK-21 cells depends on receptor subtype, GRK and host. The endpoint is loss of surface ligand binding, not direct phosphorylation of every receptor. - id: PMID:19478075 title: GRK5 deficiency leads to reduced hippocampal acetylcholine level via impaired presynaptic M2/M4 autoreceptor desensitization. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. GRK5-deficient mouse hippocampal slices and a cholinergic cell line support M2/M4-dependent feedback and altered receptor internalization; human presynaptic physiology is a homologous inference. findings: - statement: GRK5-deficient mouse hippocampal slices and a cholinergic cell line support M2/M4-dependent feedback and altered receptor internalization; human presynaptic physiology is a homologous inference. - id: PMID:19478087 title: Structural determinants of G-protein alpha subunit selectivity by regulator of G-protein signaling 2 (RGS2). full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Wild-type RGS2 preferentially accelerates Gq GTP hydrolysis; engineered RGS2 variants gain Gi-directed activity. Mutant properties are not attributed to native RGS2. findings: - statement: Wild-type RGS2 preferentially accelerates Gq GTP hydrolysis; engineered RGS2 variants gain Gi-directed activity. Mutant properties are not attributed to native RGS2. - id: PMID:8756726 title: GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. RGS4 accelerates Gi-family GTP hydrolysis; the reported substrate distinction from Gs supports context-specific GAP activity rather than an RGS-intrinsic GTPase. findings: - statement: RGS4 accelerates Gi-family GTP hydrolysis; the reported substrate distinction from Gs supports context-specific GAP activity rather than an RGS-intrinsic GTPase. - id: PMID:8508928 title: The human muscarinic M1 acetylcholine receptor, when express in CHO cells, activates and downregulates both Gq alpha and G11 alpha equally and non-selectively. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human M1 expressed in CHO cells activates/downregulates endogenous Gq and G11. The receptor is human, while host G-protein assays are not human-sequence-specific. findings: - statement: Human M1 expressed in CHO cells activates/downregulates endogenous Gq and G11. The receptor is human, while host G-protein assays are not human-sequence-specific. - id: PMID:11181437 title: 'G(q/11) and G(i/o) activation profiles in CHO cells expressing human muscarinic acetylcholine receptors: dependence on agonist as well as receptor-subtype.' full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. Human M1-M4 expressed in CHO cells activate different G-protein repertoires depending on agonist and receptor subtype. GTPgammaS binding does not itself establish every downstream cyclase response. findings: - statement: Human M1-M4 expressed in CHO cells activate different G-protein repertoires depending on agonist and receptor subtype. GTPgammaS binding does not itself establish every downstream cyclase response. - id: PMID:10869390 title: Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment is restricted to the cached abstract, even if additional full text is available. AChE-null mouse survival with developmental and physiological abnormalities supports partial compensatory hydrolysis; AChE is principal rather than universally indispensable for all transmission. findings: - statement: AChE-null mouse survival with developmental and physiological abnormalities supports partial compensatory hydrolysis; AChE is principal rather than universally indispensable for all transmission. - id: PMID:10531434 title: Multiorgan autonomic dysfunction in mice lacking the beta2 and the beta4 subunits of neuronal nicotinic acetylcholine receptors. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Mouse beta2/beta4 knockout physiology distinguishes autonomic ganglionic receptor contributions and partial functional compensation. It does not license arbitrary human neuronal subunit combinations. findings: - statement: Mouse beta2/beta4 knockout physiology distinguishes autonomic ganglionic receptor contributions and partial functional compensation. It does not license arbitrary human neuronal subunit combinations. - id: PMID:10649566 title: Identification and characterization of the high-affinity choline transporter. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Cloning and transport assays identify nematode CHO-1 and rat CHT1; species and expression claims remain confined to those experiments. Human CHT1 is established separately. findings: - statement: Cloning and transport assays identify nematode CHO-1 and rat CHT1; species and expression claims remain confined to those experiments. Human CHT1 is established separately. - id: PMID:11172068 title: Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Human CHAT mutations cause episodic-apnea myasthenic syndrome; recombinant mutant kinetics and preserved receptor abundance distinguish defective acetylcholine synthesis from primary receptor deficiency. findings: - statement: Human CHAT mutations cause episodic-apnea myasthenic syndrome; recombinant mutant kinetics and preserved receptor abundance distinguish defective acetylcholine synthesis from primary receptor deficiency. - id: PMID:12944511 title: Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Mouse immunoprecipitation, knockout electrophysiology and release assays distinguish alpha6-containing terminal receptors from predominantly alpha4beta2 somatic receptors. The asterisk in composition permits additional subunits and does not establish universal human stoichiometry. findings: - statement: Mouse immunoprecipitation, knockout electrophysiology and release assays distinguish alpha6-containing terminal receptors from predominantly alpha4beta2 somatic receptors. The asterisk in composition permits additional subunits and does not establish universal human stoichiometry. - id: PMID:8798423 title: G protein-coupled receptor kinase GRK2 is a phospholipid-dependent enzyme that can be conditionally activated by G protein betagamma subunits. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Purified human M2 phosphorylation by GRK2 requires charged phospholipids. The receptor species is explicit; kinase species is not established from the abstract. This is direct kinase evidence, unlike receptor sequestration. findings: - statement: Purified human M2 phosphorylation by GRK2 requires charged phospholipids. The receptor species is explicit; kinase species is not established from the abstract. This is direct kinase evidence, unlike receptor sequestration. - id: PMID:8288567 title: Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Purified Sf9-expressed GRK5 directly phosphorylates M2, beta2-adrenergic receptor and rhodopsin. The abstract does not identify the species of every construct; the host is not treated as the protein species. findings: - statement: Purified Sf9-expressed GRK5 directly phosphorylates M2, beta2-adrenergic receptor and rhodopsin. The abstract does not identify the species of every construct; the host is not treated as the protein species. - id: PMID:17065363 title: Muscarinic M2 receptors directly activate Gq/11 and Gs G-proteins. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: Assessment restricted to the cached abstract. Human M2 expressed in CHO cells supports inhibition of forskolin-stimulated cAMP and condition-dependent Gs/Gq signaling. A canonical inhibitory branch does not mean exclusive coupling. findings: - statement: Human M2 expressed in CHO cells supports inhibition of forskolin-stimulated cAMP and condition-dependent Gs/Gq signaling. A canonical inhibitory branch does not mean exclusive coupling.