Human acetylcholine transmission and comparative receptor mechanisms

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.

MODULE:acetylcholine_signalingCOMPLETECONCRETESignaling Pathwaymodules/acetylcholine_signaling.yaml

acetylcholine receptor signaling pathwayGO:0095500 synaptic transmission, cholinergicGO:0007271

PW:0000841

acetylcholine signaling pathway

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).

PW:0000842

acetylcholine signaling pathway via nicotinic acetylcholine receptor

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.

PW:0000843

acetylcholine signaling pathway via muscarinic acetylcholine receptor

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.

GO:0095500

acetylcholine receptor signaling pathway

The GO mapping recorded for PW:0000841 in the project's module seeds (skos:relatedMatch); it covers the reception arm of the module.

GO:0007213

G protein-coupled acetylcholine receptor signaling pathway

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.

PMID:10649566

Identification and characterization of the high-affinity choline transporter.

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.

In cholinergic neurons, high-affinity choline uptake in presynaptic terminals is the rate-limiting step in acetylcholine synthesis.

PMID:31073061

Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes.

Establishes the two muscarinic coupling classes used as the variant axis of the muscarinic branch.

M1R, M3R, and M5R couple to the Gq/ 11 family, whereas M2R and M4R couple to the Gi/ o family.

PMID:10869390

Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase.

AChE is the principal terminator of cholinergic transmission.

Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses

PMID:41461581

Current authoritative nomenclature describes preferred coupling classes, not exclusive pairing in all physiological or experimental contexts.

M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins.

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.

56Nodes

21Parts

9Variant Sets

34Variants

38Annotons

15Connections

Derived QC

Recommended-field compliance

96.1% recommended fields populated

knowledge_gaps[0].provenance[0] · reference_section_type (0/1)
knowledge_gaps[1].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:acetylcholine_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

22 gene-function check(s) reflected in core functions · 0 conflict(s) · 22 evidence or coverage gap(s) (60 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
slc5a7_choline_uptake	SLC5A7 (CHT1) UniProtKB:Q9GZV3 Gene	choline:sodium symporter activity GO:0005307	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
chat_ach_synthesis	CHAT UniProtKB:P28329 Gene	choline O-acetyltransferase activity GO:0004102	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nachr_muscle_adult_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_muscle_fetal_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha4beta2_2_3_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha4beta2_3_2_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha4beta2_alpha5_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha2beta2_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha6beta2beta3_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha4alpha6beta2beta3_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha3beta4_base_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nachr_alpha3beta4_alpha5_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
alpha7_nachr_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
alpha9alpha10_nachr_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
m1_m3_m5_receptor_chrm1	CHRM1 (M1) UniProtKB:P11229 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m1_m3_m5_receptor_chrm3	CHRM3 (M3) UniProtKB:P20309 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m1_m3_m5_receptor_chrm5	CHRM5 (M5) UniProtKB:P08912 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g_alpha_q_11_gnaq	GNAQ UniProtKB:P50148 Gene	G protein activity GO:0003925	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g_alpha_q_11_gna11	GNA11 UniProtKB:P29992 Gene	G protein activity GO:0003925	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m2_m4_receptor_chrm2	CHRM2 (M2) UniProtKB:P08172 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m2_m4_receptor_chrm4	CHRM4 (M4) UniProtKB:P08173 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g_alpha_i_o_gnai1	GNAI1 UniProtKB:P63096 Gene	G protein activity GO:0003925	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g_alpha_i_o_gnai2	GNAI2 UniProtKB:P04899 Gene	G protein activity GO:0003925	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m2_go_receptor	CHRM2 UniProtKB:P08172 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m2_go_switch	GNAO1 UniProtKB:P09471 Gene	G protein activity GO:0003925	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
g_alpha_14_context	GNA14 UniProtKB:O95837 Gene	G protein activity GO:0003925	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m1_m3_g14_receptor_chrm1	CHRM1 (M1) UniProtKB:P11229 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
m1_m3_g14_receptor_chrm3	CHRM3 (M3) UniProtKB:P20309 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ache_hydrolysis	ACHE UniProtKB:P22303 Gene	acetylcholinesterase activity GO:0003990	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grk2_machr	GRK2 (beta-ARK1, Adrbk1) UniProtKB:P25098 Gene	G protein-coupled receptor kinase activity GO:0004703	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grk5_autoreceptor	GRK5 UniProtKB:P34947 Gene	G protein-coupled receptor kinase activity GO:0004703	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rgs2_gq_gap	RGS2 UniProtKB:P41220 Gene	GTPase activator activity GO:0005096	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rgs4_gi_gap	RGS4 UniProtKB:P49798 Gene	GTPase activator activity GO:0005096	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_rgs6_gnb5_gap	PROTEIN_COMPLEX Gene	GTPase activator activity GO:0005096	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
rat_hair_cell_receptor_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
chicken_hair_cell_receptor_channel	PROTEIN_COMPLEX Gene	acetylcholine-gated monoatomic cation-selective channel activity GO:0022848	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
mouse_m2_receptor	Chrm2 UniProtKB:Q9ERZ4 Gene	G protein-coupled acetylcholine receptor activity GO:0016907	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mouse_rgs6_gnb5_gap	PROTEIN_COMPLEX Gene	GTPase activator activity GO:0005096	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
slc5a7_choline_uptake	SLC5A7 (CHT1) lineage PANTHER:PTHR45897:SF2 Family	choline:sodium symporter activity GO:0005307	Family Review Missing No supported structured family review is available for PANTHER:PTHR45897:SF2.
chat_ach_synthesis	CHAT lineage PANTHER:PTHR22589:SF14 Family	choline O-acetyltransferase activity GO:0004102	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0004102.
m1_m3_m5_receptor_chrm1	CHRM1 lineage PANTHER:PTHR24247:SF182 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF182.
m1_m3_m5_receptor_chrm3	CHRM3 lineage PANTHER:PTHR24247:SF183 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF183.
m1_m3_m5_receptor_chrm5	CHRM5 lineage PANTHER:PTHR24247:SF209 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF209.
g_alpha_q_11_gnaq	GNAQ lineage PANTHER:PTHR10218:SF329 Family	G protein activity GO:0003925	Family Review Missing No supported structured family review is available for PANTHER:PTHR10218:SF329.
g_alpha_q_11_gna11	GNA11 lineage PANTHER:PTHR10218:SF328 Family	G protein activity GO:0003925	Family Review Missing No supported structured family review is available for PANTHER:PTHR10218:SF328.
m2_m4_receptor_chrm2	CHRM2 lineage PANTHER:PTHR24247:SF207 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF207.
m2_m4_receptor_chrm4	CHRM4 lineage PANTHER:PTHR24247:SF180 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF180.
g_alpha_i_o_gnai1	GNAI1 lineage PANTHER:PTHR10218:SF359 Family	G protein activity GO:0003925	Family Review Missing No supported structured family review is available for PANTHER:PTHR10218:SF359.
g_alpha_i_o_gnai2	GNAI2 lineage PANTHER:PTHR10218:SF73 Family	G protein activity GO:0003925	Family Review Missing No supported structured family review is available for PANTHER:PTHR10218:SF73.
m2_go_receptor	CHRM2 lineage PANTHER:PTHR24247:SF207 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF207.
m2_go_switch	GNAO1 lineage PANTHER:PTHR10218:SF361 Family	G protein activity GO:0003925	Family Review Missing No supported structured family review is available for PANTHER:PTHR10218:SF361.
g_alpha_14_context	GNA14 exemplar within the G-alpha family PANTHER:PTHR10218:SF213 Family	G protein activity GO:0003925	Family Review Missing No supported structured family review is available for PANTHER:PTHR10218:SF213.
m1_m3_g14_receptor_chrm1	CHRM1 lineage PANTHER:PTHR24247:SF182 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF182.
m1_m3_g14_receptor_chrm3	CHRM3 lineage PANTHER:PTHR24247:SF183 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF183.
ache_hydrolysis	ACHE lineage PANTHER:PTHR43918:SF11 Family	acetylcholinesterase activity GO:0003990	Family Review Missing No supported structured family review is available for PANTHER:PTHR43918:SF11.
grk2_machr	GRK2 (beta-ARK1, Adrbk1) lineage PANTHER:PTHR24355:SF22 Family	G protein-coupled receptor kinase activity GO:0004703	Family Review Missing No supported structured family review is available for PANTHER:PTHR24355:SF22.
grk5_autoreceptor	GRK5 lineage PANTHER:PTHR24355:SF27 Family	G protein-coupled receptor kinase activity GO:0004703	Family Review Missing No supported structured family review is available for PANTHER:PTHR24355:SF27.
rgs2_gq_gap	RGS2 lineage PANTHER:PTHR10845:SF43 Family	GTPase activator activity GO:0005096	Family Review Missing No supported structured family review is available for PANTHER:PTHR10845:SF43.
rgs4_gi_gap	RGS4 lineage PANTHER:PTHR10845:SF184 Family	GTPase activator activity GO:0005096	Family Review Missing No supported structured family review is available for PANTHER:PTHR10845:SF184.
mouse_m2_receptor	Chrm2 lineage PANTHER:PTHR24247:SF207 Family	G protein-coupled acetylcholine receptor activity GO:0016907	Family Review Missing No supported structured family review is available for PANTHER:PTHR24247:SF207.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

ach_hydrolysis ⊣ ach_reception [closed]
ach_hydrolysis is regulated by ach_release: feedback loop closed
machr_gi_activation ⊣ ach_release [input]
machr_gi_activation is a negative regulator with no upstream edge (not described as feedback)
ach_muscarinic_termination ⊣ muscarinic_reception [input]
ach_muscarinic_termination is a negative regulator with no upstream edge (not described as feedback)
grk5_autoreceptor ⊣ machr_gi_activation [input]
grk5_autoreceptor is a negative regulator with no upstream edge (not described as feedback)
mouse_rgs6_regulation ⊣ mouse_m2_signal [input]
mouse_rgs6_regulation is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (43/43 grounded genes reviewed)

15 complete review(s) · 0 with deep research · 0 missing review · 43 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ACHE P22303	✓	47/53	✗
CHAT P28329	✓	✓	✗
CHRM1 P11229	✓	51/52	✗
CHRM2 P08172	✓	62/64	✗
Chrm2 Q9ERZ4	✓	49/54	✗
CHRM3 P20309	✓	49/52	✗
CHRM4 P08173	✓	✓	✗
CHRM5 P08912	✓	✓	✗
CHRNA1 P02708	✓	72/74	✗
CHRNA10 Q9GZZ6	✓	39/44	✗
CHRNA10 Q9I8C7	✓	✓	✗
Chrna10 Q9JLB5	✓	46/48	✗
CHRNA2 Q15822	✓	51/55	✗
CHRNA3 P32297	✓	72/80	✗
CHRNA4 P43681	✓	95/100	✗
CHRNA5 P30532	✓	52/55	✗
CHRNA6 Q15825	✓	51/54	✗
CHRNA7 P36544	✓	147/151	✗
Chrna9 P43144	✓	53/54	✗
CHRNA9 Q9PTS8	✓	✓	✗
CHRNA9 Q9UGM1	✓	38/39	✗
CHRNB1 P11230	✓	57/60	✗
CHRNB2 P17787	✓	116/122	✗
CHRNB3 Q05901	✓	50/51	✗
CHRNB4 P30926	✓	83/87	✗
CHRND Q07001	✓	✓	✗
CHRNE Q04844	✓	✓	✗
CHRNG P07510	✓	✓	✗
GNA11 P29992	✓	74/82	✗
GNA14 O95837	✓	62/64	✗
GNAI1 P63096	✓	140/146	✗
GNAI2 P04899	✓	✓	✗
GNAO1 P09471	✓	✓	✗
GNAQ P50148	✓	111/121	✗
GNB5 O14775	✓	✓	✗
Gnb5 P62881	✓	45/46	✗
GRK2 P25098	✓	✓	✗
GRK5 P34947	✓	34/37	✗
RGS2 P41220	✓	61/63	✗
RGS4 P49798	✓	33/35	✗
RGS6 P49758	✓	✓	✗
Rgs6 Q9Z2H2	✓	✓	✗
SLC5A7 Q9GZV3	✓	✓	✗

Tree

Acetylcholine signalingSignaling Pathwayacetylcholine_signaling

Parts
1. 1. high-affinity choline uptake into the cholinergic terminal
2. CHT1 (SLC5A7) sodium-coupled choline uptakeTransport Stepach_choline_uptake
  
  Annotons
  - CHT1 (SLC5A7) choline:sodium symport Gene Product: SLC5A7 (CHT1)
3. 2. acetylcholine synthesis
4. CHAT synthesis of acetylcholine from acetyl-CoA and cholineReactionach_synthesis
  
  Annotons
  - CHAT choline O-acetyltransferase activity Gene Product: CHAT
5. 3. vesicular acetylcholine loading
6. VAChT (SLC18A3) loading of ACh into synaptic vesiclesach_vesicle_loading
7. 4. calcium-triggered vesicular ACh release
8. Synaptic vesicle exocytosis of AChach_release
9. 5. acetylcholine reception
10. Nicotinic and muscarinic acetylcholine receptorsSignaling Pathwayach_reception
  
  Variants
  1. Receptor class by receptor class (ionotropic vs metabotropic) (One Or More)
    
    Nicotinic ACh receptor (ligand-gated cation channel) signallingSignaling Pathwaynicotinic_reception
    
    Variants
    
    Nicotinic receptor subtype by subunit composition / tissue (One Or More)
    
    Adult human muscle nAChRProtein Complexnachr_muscle_adult
    
    Annotons
    
    Adult human muscle nAChR cation-channel activity Protein Complex: Adult human muscle nAChR
    
    Fetal human muscle nAChRProtein Complexnachr_muscle_fetal
    
    Annotons
    
    Fetal human muscle nAChR cation-channel activity Protein Complex: Fetal human muscle nAChR
    
    Human (alpha4)2(beta2)3 nAChRProtein Complexnachr_alpha4beta2_2_3
    
    Annotons
    
    Human (alpha4)2(beta2)3 nAChR cation-channel activity Protein Complex: Human (alpha4)2(beta2)3 nAChR
    
    Human (alpha4)3(beta2)2 nAChRProtein Complexnachr_alpha4beta2_3_2
    
    Annotons
    
    Human (alpha4)3(beta2)2 nAChR cation-channel activity Protein Complex: Human (alpha4)3(beta2)2 nAChR
    
    Human (alpha4beta2)2 alpha5 nAChRProtein Complexnachr_alpha4beta2_alpha5
    
    Annotons
    
    Human (alpha4beta2)2 alpha5 nAChR cation-channel activity Protein Complex: Human (alpha4beta2)2 alpha5 nAChR
    
    Human alpha2beta2 nAChRProtein Complexnachr_alpha2beta2
    
    Annotons
    
    Human alpha2beta2 nAChR cation-channel activity Protein Complex: Human alpha2beta2 nAChR
    
    Human (alpha6beta2)2 beta3 nAChRProtein Complexnachr_alpha6beta2beta3
    
    Annotons
    
    Human (alpha6beta2)2 beta3 nAChR cation-channel activity Protein Complex: Human (alpha6beta2)2 beta3 nAChR
    
    Human (alpha4beta2)(alpha6beta2) beta3 nAChRProtein Complexnachr_alpha4alpha6beta2beta3
    
    Annotons
    
    Human (alpha4beta2)(alpha6beta2) beta3 nAChR cation-channel activity Protein Complex: Human (alpha4beta2)(alpha6beta2) beta3 nAChR
    
    Human alpha3beta4 nAChRProtein Complexnachr_alpha3beta4_base
    
    Annotons
    
    Human alpha3beta4 nAChR cation-channel activity Protein Complex: Human alpha3beta4 nAChR
    
    Human alpha3beta4alpha5 nAChRProtein Complexnachr_alpha3beta4_alpha5
    
    Annotons
    
    Human alpha3beta4alpha5 nAChR cation-channel activity Protein Complex: Human alpha3beta4alpha5 nAChR
    
    Homomeric alpha7 nAChRProtein Complexnachr_alpha7
    
    Annotons
    
    alpha7 nAChR ACh-gated cation channel Protein Complex: human alpha7 homopentamer
    
    alpha9alpha10 nAChRProtein Complexnachr_alpha9alpha10
    
    Annotons
    
    alpha9alpha10 nAChR ACh-gated cation channel Protein Complex: alpha9alpha10 nicotinic receptor
    
    Muscarinic ACh receptor (GPCR) signallingSignaling Pathwaymuscarinic_reception
    
    Variants
    
    Muscarinic G protein coupling class by G protein family coupled (One Or More)
    
    M1/M3/M5 -> Gq/11 -> PLC betaSignaling Pathwaymachr_gq_branch
    
    Parts
    
    1. receptor and Gq/11 activation
    
    M1/M3/M5 activate G alpha q/11Regulatory Stepmachr_gq_activation
    
    Parts
    
    1. M1/M3/M5 G protein-coupled ACh receptors
    
    M1/M3/M5 G protein-coupled ACh receptorsRegulatory Stepm1_m3_m5_receptor
    
    Variants
    
    Named member alternatives by gene product (One Or More)
    
    CHRM1m1_m3_m5_receptor_chrm1_implementation
    
    Annotons
    
    CHRM1 — M1/M3/M5 G protein-coupled ACh receptors Gene Product: CHRM1 (M1)
    
    CHRM3m1_m3_m5_receptor_chrm3_implementation
    
    Annotons
    
    CHRM3 — M1/M3/M5 G protein-coupled ACh receptors Gene Product: CHRM3 (M3)
    
    CHRM5m1_m3_m5_receptor_chrm5_implementation
    
    Annotons
    
    CHRM5 — M1/M3/M5 G protein-coupled ACh receptors Gene Product: CHRM5 (M5)
    
    2. G alpha q/11 family switch
    
    G alpha q/11 family switchRegulatory Stepg_alpha_q_11
    
    Variants
    
    Named member alternatives by gene product (One Or More)
    
    GNAQg_alpha_q_11_gnaq_implementation
    
    Annotons
    
    GNAQ — G alpha q/11 family switch Gene Product: GNAQ
    
    GNA11g_alpha_q_11_gna11_implementation
    
    Annotons
    
    GNA11 — G alpha q/11 family switch Gene Product: GNA11
    
    2. PLC beta, IP3/calcium and DAG/PKC effector cascade
    
    PLC beta hydrolysis of PIP2 (shared Gq effector)machr_gq_plc_effector
    
    M2/M4 Gi signaling and inhibitory cAMP outputSignaling Pathwaymachr_gi_branch
    
    Parts
    
    1. receptor and Gi/o activation
    
    M2/M4 activate G alpha i/oRegulatory Stepmachr_gi_activation
    
    Parts
    
    1. M2/M4 G protein-coupled ACh receptors
    
    M2/M4 G protein-coupled ACh receptorsRegulatory Stepm2_m4_receptor
    
    Variants
    
    Named member alternatives by gene product (One Or More)
    
    CHRM2m2_m4_receptor_chrm2_implementation
    
    Annotons
    
    CHRM2 — M2/M4 G protein-coupled ACh receptors Gene Product: CHRM2 (M2)
    
    CHRM4m2_m4_receptor_chrm4_implementation
    
    Annotons
    
    CHRM4 — M2/M4 G protein-coupled ACh receptors Gene Product: CHRM4 (M4)
    
    2. Gi alpha switches
    
    Gi alpha switchesRegulatory Stepg_alpha_i_o
    
    Variants
    
    Named member alternatives by gene product (One Or More)
    
    GNAI1g_alpha_i_o_gnai1_implementation
    
    Annotons
    
    GNAI1 — Gi alpha switches Gene Product: GNAI1
    
    GNAI2g_alpha_i_o_gnai2_implementation
    
    Annotons
    
    GNAI2 — Gi alpha switches Gene Product: GNAI2
    
    2. inhibited adenylyl cyclase step optional
    
    Adenylyl cyclase effector interfacemachr_gi_adenylyl_cyclase
    
    M2-Go receptionSignaling Pathwaymachr_go_branch
    
    Annotons
    
    M2 receptor coupled to Go Gene Product: CHRM2
    
    Go alpha downstream of M2 Gene Product: GNAO1
    
    M1/M3-G14 experimental couplingSignaling Pathwaymachr_g14_branch
    
    Annotons
    
    G14 activation in the M1/M3 BRET system Gene Product: GNA14
    
    Parts
    
    1. M1/M3 coupling to G14 in an expression assay
    
    M1/M3 coupling to G14 in an expression assayRegulatory Stepm1_m3_g14_receptor
    
    Variants
    
    Named member alternatives by gene product (One Or More)
    
    CHRM1m1_m3_g14_receptor_chrm1_implementation
    
    Annotons
    
    CHRM1 — M1/M3 coupling to G14 in an expression assay Gene Product: CHRM1 (M1)
    
    CHRM3m1_m3_g14_receptor_chrm3_implementation
    
    Annotons
    
    CHRM3 — M1/M3 coupling to G14 in an expression assay Gene Product: CHRM3 (M3)
11. 6. acetylcholine hydrolysis and signal termination
12. AChE hydrolysis of acetylcholine in the synaptic cleftReactionach_hydrolysis
  
  Annotons
  - ACHE acetylcholinesterase activity Gene Product: ACHE
13. 7. muscarinic receptor desensitisation and G protein deactivation optional
14. GRK desensitisation of mAChRs and RGS acceleration of G alpha GTP hydrolysisRegulatory Stepach_muscarinic_termination
  
  Variants
  1. Context-dependent regulatory mechanisms by regulator mechanism (One Or More)
    
    GRK2 phosphorylation of muscarinic receptorsgrk2_machr_regulatory_mechanism
    
    Annotons
    
    GRK2 phosphorylation of muscarinic receptors Gene Product: GRK2 (beta-ARK1, Adrbk1)
    
    GRK5 M2 phosphorylation and muscarinic desensitizationgrk5_autoreceptor_regulatory_mechanism
    
    Annotons
    
    GRK5 M2 phosphorylation and muscarinic desensitization Gene Product: GRK5
    
    RGS2 GTPase-activating activity on G alpha qrgs2_gq_gap_regulatory_mechanism
    
    Annotons
    
    RGS2 GTPase-activating activity on G alpha q Gene Product: RGS2
    
    RGS4 GAP activity on Girgs4_gi_gap_regulatory_mechanism
    
    Annotons
    
    RGS4 GAP activity on Gi Gene Product: RGS4
    
    RGS6–GNB5 GAP complexhuman_rgs6_gnb5_gap_regulatory_mechanism
    
    Annotons
    
    RGS6–GNB5 GAP complex Protein Complex: RGS6–GNB5 complex
15. 8. comparative hair-cell receptor capacity optional
16. Rat alpha9/alpha10 receptor comparatorProtein Complexrat_hair_cell_receptor
  
  Annotons
  - Rat alpha9/alpha10 receptor comparator cation-channel activity Protein Complex: Rat alpha9/alpha10 receptor comparator
17. 9. comparative hair-cell receptor capacity optional
18. Chicken alpha9/alpha10 receptor comparatorProtein Complexchicken_hair_cell_receptor
  
  Annotons
  - Chicken alpha9/alpha10 receptor comparator cation-channel activity Protein Complex: Chicken alpha9/alpha10 receptor comparator
19. 10. native mouse cardiac regulatory comparison optional
20. Mouse Rgs6–Gnb5 regulation of cardiac M2 signalingRegulatory Stepmouse_cardiac_regulation
  
  Parts
  1. 1. M2-driven cardiac signaling
  2. M2-initiated cardiac responsemouse_m2_signal
    
    Annotons
    
    Mouse M2 muscarinic receptor Gene Product: Chrm2
  3. 2. Rgs6-Gnb5 temporal regulation
  4. Rgs6-Gnb5 GAP complexmouse_rgs6_regulation
    
    Annotons
    
    Rgs6–Gnb5 GAP complex Protein Complex: Rgs6–Gnb5 complex

Details

Context

Homo sapiensNCBITaxon:9606 Rattus norvegicusNCBITaxon:10116 Gallus gallusNCBITaxon:9031 Mus musculusNCBITaxon:10090

cholinergic synapseGO:0098981

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.

Acetylcholine signalingSignaling Pathwayacetylcholine_signaling

acetylcholine receptor signaling pathwayGO:0095500 synaptic transmission, cholinergicGO:0007271

Context

Homo sapiensNCBITaxon:9606 Rattus norvegicusNCBITaxon:10116 Gallus gallusNCBITaxon:9031 Mus musculusNCBITaxon:10090

cholinergic synapseGO:0098981

Connections

ach_choline_uptake -> ach_synthesis Provides Input For

Transported choline is the substrate acetylated by CHAT. This links independently demonstrated transport and catalytic reactions, without asserting a transporter-enzyme complex.

PMID:11027560

Human transporter expression establishes choline uptake.

PMID:17144655

Human CHAT structures define choline and acetyl-CoA recognition and the acetyl-transfer mechanism.

ach_synthesis -> ach_vesicle_loading Provides Input For

CHAT-generated cytosolic acetylcholine is available as substrate for VAChT loading; chemical continuity is inferred from the independently measured reactions.

PMID:17144655

CHAT produces acetylcholine from choline and acetyl-CoA.

PMID:8910293

Human VAChT expressed in PC-12 cells mediates ATP/proton-gradient-dependent vesicular acetylcholine uptake.

ach_vesicle_loading -> ach_release Provides Input For

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.

PMID:8910293

Human VAChT confers vesicular acetylcholine accumulation in a rat cell line.

PMID:10526333

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.

ach_release -> ach_reception Provides Input For

Extracellular acetylcholine activates the receptor implementations. Native release and recombinant human receptor responses provide complementary evidence, rather than a single reconstructed human synapse.

PMID:10526333

Native worm neuromuscular electrophysiology connects evoked vesicular release to cholinergic postsynaptic responses.

PMID:8788941

Recombinant human adult and fetal muscle receptor assemblies respond to acetylcholine.

PMID:11181437

Agonist-stimulated human muscarinic receptors expressed in CHO cells activate G proteins with subtype- and agonist-dependent profiles.

ach_release -> ach_hydrolysis Provides Input For

Released acetylcholine is an extracellular substrate for acetylcholinesterase; this is a chemical substrate relation.

PMID:1517212

Human acetylcholinesterase catalytic-triad substitutions abolish enzymatic activity while preserving secretion and folding.

file:human/ACHE/ACHE-uniprot.txt

Publication-linked curated reaction specifies acetylcholine hydrolysis to choline and acetate.

acetylcholine + H2O = choline + acetate + H(+)

ach_hydrolysis -> ach_reception Negatively Regulates

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.

PMID:10869390

AChE-null mice survive with substantial physiological abnormalities and compensatory hydrolysis; the study supports a principal, not exclusive, termination role.

PMID:1517212

Human mutagenesis independently establishes the catalytic activity underlying agonist removal.

ach_hydrolysis -> ach_choline_uptake Provides Input For

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.

file:human/ACHE/ACHE-uniprot.txt

Curated catalytic reaction produces choline.

acetylcholine + H2O = choline + acetate + H(+)

PMID:11027560

Human CHT1 transports extracellular choline with high affinity.

machr_gi_activation -> ach_release Negatively Regulates

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.

PMID:19478075

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.

ach_muscarinic_termination -> muscarinic_reception Negatively Regulates

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.

PMID:9495886

Coexpression experiments measure receptor sequestration with subtype and cell-line dependence.

PMID:8756726

RGS4 accelerates Gi-family GTP hydrolysis.

PMID:19478087

Wild-type RGS2 has potent Gq-directed GAP activity.

PMID:20884879

Native mouse Rgs6-Gnb5 controls deactivation kinetics of the M2-driven cardiac response.

grk5_autoreceptor -> machr_gi_activation Negatively Regulates

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.

PMID:19478075

Mouse hippocampal slices lacking GRK5 show reduced M2/M4 internalization and stronger inhibitory feedback on acetylcholine release.

PMID:9495886

GRK5 coexpression facilitates human M2 sequestration in BHK-21 cells; this is not a universal effect across receptor subtypes or host cells.

Part 1: high-affinity choline uptake into the cholinergic terminal

CHT1 (SLC5A7) sodium-coupled choline uptakeTransport Stepach_choline_uptake

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

CHT1 (SLC5A7) choline:sodium symport

slc5a7_choline_uptake

Participant: Gene Product: SLC5A7 (CHT1)

Gene Product:

SLC5A7 (CHT1)UniProtKB:Q9GZV3

Family:

SLC5A7 (CHT1) lineagePANTHER:PTHR45897:SF2 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.

Representative Members: SLC5A7 (CHT1)UniProtKB:Q9GZV3

Function

choline:sodium symporter activityGO:0005307

Substrates: extracellular cholineCHEBI:15354

Processes

choline transportGO:0015871

Locations

presynaptic membraneGO:0042734

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.

PMID:11027560

Human CHT cloned from spinal cord produces saturable sodium/chloride-dependent choline uptake in COS-7 membrane vesicles.

Expression of hCHT cDNA in COS-7 cells results in saturable, Na(+)/Cl(-)-dependent choline uptake

PMID:10649566

Original comparative CHT1 characterization; the expression restriction reported here applies to its experimental context and is not a universal assertion about human SLC5A7.

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.

PMID:10649566

Original comparative CHT1 characterization; the expression restriction reported here applies to its experimental context and is not a universal assertion about human SLC5A7.

The characteristics of CHT1-mediated choline uptake essentially match those of high-affinity choline uptake in rat brain synaptosomes.

Part 2: acetylcholine synthesis

CHAT synthesis of acetylcholine from acetyl-CoA and cholineReactionach_synthesis

Cytosolic CHAT transfers the acetyl group of acetyl-CoA to choline, giving ACh and CoA; its presence defines a cholinergic neuron.

Context

Homo sapiensNCBITaxon:9606

Annotons

CHAT choline O-acetyltransferase activity

chat_ach_synthesis

Participant: Gene Product: CHAT

Gene Product:

CHATUniProtKB:P28329

Family:

CHAT lineagePANTHER:PTHR22589:SF14 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.

Representative Members: CHATUniProtKB:P28329

Function

choline O-acetyltransferase activityGO:0004102

Substrates: acetyl-CoACHEBI:15351 cholineCHEBI:15354

Products: acetylcholineCHEBI:15355

Processes

acetylcholine biosynthetic processGO:0008292

Locations

cytosolGO:0005829

The only ACh-synthesising enzyme of cholinergic neurons; this matches the core function in the CHAT gene review.

PMID:17144655

CHAT synthesises ACh from choline and acetyl-CoA.

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.

PMID:11172068

Catalytically impaired CHAT causes a congenital myasthenic syndrome with stimulation-dependent failure of neuromuscular transmission.

Here we report that mutations in CHAT cause a congenital myasthenic syndrome associated with frequently fatal episodes of apnea (CMS-EA).

Part 3: vesicular acetylcholine loading

VAChT (SLC18A3) loading of ACh into synaptic vesiclesach_vesicle_loading

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.

Realized by module synaptic_vesicle_neurotransmitter_loading#acetylcholine_loading

Context

Homo sapiensNCBITaxon:9606

Part 4: calcium-triggered vesicular ACh release

Synaptic vesicle exocytosis of AChach_release

Included by reference to the synaptic vesicle exocytosis module (docking, priming and calcium-triggered SNARE fusion), which is transmitter-agnostic.

Realized by module synaptic_vesicle_exocytosis

Context

Homo sapiensNCBITaxon:9606

Part 5: acetylcholine reception

Nicotinic and muscarinic acetylcholine receptorsSignaling Pathwayach_reception

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.

Context

Homo sapiensNCBITaxon:9606

Variant set: Receptor class by receptor class (ionotropic vs metabotropic) (One Or More)

Many cholinergic targets, e.g. autonomic ganglia and hippocampal neurons, express both classes, hence ONE_OR_MORE.

Nicotinic ACh receptor (ligand-gated cation channel) signallingSignaling Pathwaynicotinic_reception

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.

PMID:32272141

Structural review supports limited subunit combinations, composition-dependent binding interfaces and channel properties.

assemble in limited combinations

PMID:34867208

Alpha9/alpha10-mediated hair-cell signaling separates cation influx from downstream inhibition.

Variant set: Nicotinic receptor subtype by subunit composition / tissue (One Or More)

Adult human muscle nAChRProtein Complexnachr_muscle_adult

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Adult human muscle nAChR cation-channel activity

nachr_muscle_adult_channel

Participant: Protein Complex: Adult human muscle nAChR

Protein Complex:

Adult human muscle nAChRGO:0005892

Active units:

alpha1 subunit (two copies)2

Participant: Gene Product: CHRNA1

Gene Product:

CHRNA1UniProtKB:P02708

Family:

CHRNA1 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA1UniProtKB:P02708

Role: Principal (+) face of both ACh binding sites.

beta1 subunit1

Participant: Gene Product: CHRNB1

Gene Product:

CHRNB1UniProtKB:P11230

Family:

CHRNB1 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNB1UniProtKB:P11230

Role: Non-binding structural subunit of the pentamer.

delta subunit1

Participant: Gene Product: CHRND

Gene Product:

CHRNDUniProtKB:Q07001

Family:

CHRND nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNDUniProtKB:Q07001

Role: Complementary (-) face of one ACh site.

epsilon subunit (adult)1

Participant: Gene Product: CHRNE

Gene Product:

CHRNEUniProtKB:Q04844

Family:

CHRNE nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNEUniProtKB:Q04844

Role: Complementary face of the second ACh site in adult receptors; confers short bursts and high conductance.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

neuromuscular synaptic transmissionGO:0007274

Locations

postsynaptic membraneGO:0045211 neuromuscular junctionGO:0031594

PMID:8788941

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.

adult (alpha 2 beta delta epsilon) and fetal (alpha 2 beta delta gamma)

Fetal human muscle nAChRProtein Complexnachr_muscle_fetal

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Fetal human muscle nAChR cation-channel activity

nachr_muscle_fetal_channel

Participant: Protein Complex: Fetal human muscle nAChR

Protein Complex:

Fetal human muscle nAChRGO:0005892

Active units:

alpha1 subunit (two copies)2

Participant: Gene Product: CHRNA1

Gene Product:

CHRNA1UniProtKB:P02708

Family:

Representative Members: CHRNA1UniProtKB:P02708

Role: Principal (+) face of both ACh binding sites.

beta1 subunit1

Participant: Gene Product: CHRNB1

Gene Product:

CHRNB1UniProtKB:P11230

Family:

Representative Members: CHRNB1UniProtKB:P11230

Role: Non-binding structural subunit of the pentamer.

delta subunit1

Participant: Gene Product: CHRND

Gene Product:

CHRNDUniProtKB:Q07001

Family:

Representative Members: CHRNDUniProtKB:Q07001

Role: Complementary (-) face of one ACh site.

gamma subunit (fetal)1

Participant: Gene Product: CHRNG

Gene Product:

CHRNGUniProtKB:P07510

Family:

CHRNG nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNGUniProtKB:P07510

Role: Replaces epsilon in fetal receptors; longer openings, lower conductance.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

neuromuscular synaptic transmissionGO:0007274

Locations

postsynaptic membraneGO:0045211 neuromuscular junctionGO:0031594

PMID:8788941

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.

adult (alpha 2 beta delta epsilon) and fetal (alpha 2 beta delta gamma)

Human (alpha4)2(beta2)3 nAChRProtein Complexnachr_alpha4beta2_2_3

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human (alpha4)2(beta2)3 nAChR cation-channel activity

nachr_alpha4beta2_2_3_channel

Participant: Protein Complex: Human (alpha4)2(beta2)3 nAChR

Protein Complex:

Human (alpha4)2(beta2)3 nAChRGO:0005892

Active units:

alpha4 subunit2

Participant: Gene Product: CHRNA4

Gene Product:

CHRNA4UniProtKB:P43681

Family:

CHRNA4 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA4UniProtKB:P43681

Role: Principal ACh-binding subunit of alpha4beta2*.

beta2 subunit3

Participant: Gene Product: CHRNB2

Gene Product:

CHRNB2UniProtKB:P17787

Family:

CHRNB2 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNB2UniProtKB:P17787

Role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271

Locations

plasma membraneGO:0005886

PMID:27698419

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.

The α4β2 receptor is known to assemble in two functional subunit stoichiometries, 3α:2β and 2α:3β.

PMID:32272141

Structural review distinguishes the two stoichiometries and the additional alpha4/alpha4 binding interface in the alpha-rich form.

Human (alpha4)3(beta2)2 nAChRProtein Complexnachr_alpha4beta2_3_2

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human (alpha4)3(beta2)2 nAChR cation-channel activity

nachr_alpha4beta2_3_2_channel

Participant: Protein Complex: Human (alpha4)3(beta2)2 nAChR

Protein Complex:

Human (alpha4)3(beta2)2 nAChRGO:0005892

Active units:

alpha4 subunit3

Participant: Gene Product: CHRNA4

Gene Product:

CHRNA4UniProtKB:P43681

Family:

Representative Members: CHRNA4UniProtKB:P43681

Role: Principal ACh-binding subunit of alpha4beta2*.

beta2 subunit2

Participant: Gene Product: CHRNB2

Gene Product:

CHRNB2UniProtKB:P17787

Family:

Representative Members: CHRNB2UniProtKB:P17787

Role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271

Locations

plasma membraneGO:0005886

PMID:27698419

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.

The α4β2 receptor is known to assemble in two functional subunit stoichiometries, 3α:2β and 2α:3β.

PMID:32272141

Structural review distinguishes the two stoichiometries and the additional alpha4/alpha4 binding interface in the alpha-rich form.

Human (alpha4beta2)2 alpha5 nAChRProtein Complexnachr_alpha4beta2_alpha5

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human (alpha4beta2)2 alpha5 nAChR cation-channel activity

nachr_alpha4beta2_alpha5_channel

Participant: Protein Complex: Human (alpha4beta2)2 alpha5 nAChR

Protein Complex:

Human (alpha4beta2)2 alpha5 nAChRGO:0005892

Active units:

alpha4 subunit2

Participant: Gene Product: CHRNA4

Gene Product:

CHRNA4UniProtKB:P43681

Family:

Representative Members: CHRNA4UniProtKB:P43681

Role: Principal ACh-binding subunit of alpha4beta2*.

beta2 subunit2

Participant: Gene Product: CHRNB2

Gene Product:

CHRNB2UniProtKB:P17787

Family:

Representative Members: CHRNB2UniProtKB:P17787

Role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*.

alpha5 subunit1

Participant: Gene Product: CHRNA5

Gene Product:

CHRNA5UniProtKB:P30532

Family:

CHRNA5 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA5UniProtKB:P30532

Role: Accessory subunit that speeds desensitisation.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271

Locations

plasma membraneGO:0005886

PMID:20881005

Defined human alpha4/beta2/alpha5 assemblies were functionally assayed; the accessory subunit is required for this alternative but not for alpha4/beta2-only channels.

Oocytes were injected with 5 ng of the β2-α4-β2-α4 concatamer cRNA and 2.5 ng of α5 cRNA.

Human alpha2beta2 nAChRProtein Complexnachr_alpha2beta2

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human alpha2beta2 nAChR cation-channel activity

nachr_alpha2beta2_channel

Participant: Protein Complex: Human alpha2beta2 nAChR

Protein Complex:

Human alpha2beta2 nAChRGO:0005892

Active units:

alpha2 subunit

Participant: Gene Product: CHRNA2

Gene Product:

CHRNA2UniProtKB:Q15822

Family:

CHRNA2 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA2UniProtKB:Q15822

Role: Alternative principal alpha subunit pairing with beta2 or beta4.

beta2 subunit

Participant: Gene Product: CHRNB2

Gene Product:

CHRNB2UniProtKB:P17787

Family:

Representative Members: CHRNB2UniProtKB:P17787

Role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271

Locations

plasma membraneGO:0005886

PMID:8906617

Human alpha2, alpha3 and alpha4 were each expressed with beta2 or beta4; these combinations gave antagonist-sensitive ACh-evoked currents.

confirming functional expression of human nicotinic receptors.

Human (alpha6beta2)2 beta3 nAChRProtein Complexnachr_alpha6beta2beta3

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human (alpha6beta2)2 beta3 nAChR cation-channel activity

nachr_alpha6beta2beta3_channel

Participant: Protein Complex: Human (alpha6beta2)2 beta3 nAChR

Protein Complex:

Human (alpha6beta2)2 beta3 nAChRGO:0005892

Active units:

alpha6 subunit2

Participant: Gene Product: CHRNA6

Gene Product:

CHRNA6UniProtKB:Q15825

Family:

CHRNA6 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA6UniProtKB:Q15825

Role: Principal subunit of presynaptic alpha6beta2* receptors.

beta2 subunit2

Participant: Gene Product: CHRNB2

Gene Product:

CHRNB2UniProtKB:P17787

Family:

Representative Members: CHRNB2UniProtKB:P17787

Role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*.

beta3 subunit1

Participant: Gene Product: CHRNB3

Gene Product:

CHRNB3UniProtKB:Q05901

Family:

CHRNB3 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNB3UniProtKB:Q05901

Role: Accessory subunit of alpha6beta2beta3 receptors.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271 presynaptic modulation of chemical synaptic transmissionGO:0099171

Locations

plasma membraneGO:0005886

PMID:20923852

Human concatameric subunits permit functional alpha6/beta2/beta3-containing receptors with defined compositions; native unlinked assembly and surface delivery remain distinct questions.

Concatameric subunits permit assembly of functional α6β2β3* AChRs with defined subunit compositions and subunit orders.

PMID:12944511

Mouse striatal immunoprecipitation and knockout studies establish related alpha6-containing receptor classes; these are comparative native evidence, not direct human stoichiometry measurements.

Human (alpha4beta2)(alpha6beta2) beta3 nAChRProtein Complexnachr_alpha4alpha6beta2beta3

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human (alpha4beta2)(alpha6beta2) beta3 nAChR cation-channel activity

nachr_alpha4alpha6beta2beta3_channel

Participant: Protein Complex: Human (alpha4beta2)(alpha6beta2) beta3 nAChR

Protein Complex:

Human (alpha4beta2)(alpha6beta2) beta3 nAChRGO:0005892

Active units:

alpha4 subunit1

Participant: Gene Product: CHRNA4

Gene Product:

CHRNA4UniProtKB:P43681

Family:

Representative Members: CHRNA4UniProtKB:P43681

Role: Principal ACh-binding subunit of alpha4beta2*.

alpha6 subunit1

Participant: Gene Product: CHRNA6

Gene Product:

CHRNA6UniProtKB:Q15825

Family:

Representative Members: CHRNA6UniProtKB:Q15825

Role: Principal subunit of presynaptic alpha6beta2* receptors.

beta2 subunit2

Participant: Gene Product: CHRNB2

Gene Product:

CHRNB2UniProtKB:P17787

Family:

Representative Members: CHRNB2UniProtKB:P17787

Role: Complementary ACh-site subunit shared by alpha4beta2* and alpha6beta2*.

beta3 subunit1

Participant: Gene Product: CHRNB3

Gene Product:

CHRNB3UniProtKB:Q05901

Family:

Representative Members: CHRNB3UniProtKB:Q05901

Role: Accessory subunit of alpha6beta2beta3 receptors.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271 presynaptic modulation of chemical synaptic transmissionGO:0099171

Locations

plasma membraneGO:0005886

PMID:20923852

Human concatameric subunits permit functional alpha6/beta2/beta3-containing receptors with defined compositions; native unlinked assembly and surface delivery remain distinct questions.

Concatameric subunits permit assembly of functional α6β2β3* AChRs with defined subunit compositions and subunit orders.

PMID:12944511

Mouse striatal immunoprecipitation and knockout studies establish related alpha6-containing receptor classes; these are comparative native evidence, not direct human stoichiometry measurements.

Human alpha3beta4 nAChRProtein Complexnachr_alpha3beta4_base

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human alpha3beta4 nAChR cation-channel activity

nachr_alpha3beta4_base_channel

Participant: Protein Complex: Human alpha3beta4 nAChR

Protein Complex:

Human alpha3beta4 nAChRGO:0005892

Active units:

alpha3 subunit

Participant: Gene Product: CHRNA3

Gene Product:

CHRNA3UniProtKB:P32297

Family:

CHRNA3 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA3UniProtKB:P32297

Role: Principal ACh-binding subunit.

beta4 subunit

Participant: Gene Product: CHRNB4

Gene Product:

CHRNB4UniProtKB:P30926

Family:

CHRNB4 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNB4UniProtKB:P30926

Role: Complementary ACh-site subunit.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271

Locations

postsynaptic membraneGO:0045211

PMID:8663494

Cloned human alpha3/beta4 with or without alpha5 reaches the oocyte surface and yields functional receptors; alpha5 speeds desensitization.

alpha5 subunits coassembled very efficiently with alpha3beta2 or alpha3beta4 combinations.

PMID:10531434

Native mouse beta-subunit knockouts establish the importance of beta4-containing receptors in autonomic ganglia; this is not a direct human copy-number measurement.

Human alpha3beta4alpha5 nAChRProtein Complexnachr_alpha3beta4_alpha5

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

Human alpha3beta4alpha5 nAChR cation-channel activity

nachr_alpha3beta4_alpha5_channel

Participant: Protein Complex: Human alpha3beta4alpha5 nAChR

Protein Complex:

Human alpha3beta4alpha5 nAChRGO:0005892

Active units:

alpha3 subunit

Participant: Gene Product: CHRNA3

Gene Product:

CHRNA3UniProtKB:P32297

Family:

Representative Members: CHRNA3UniProtKB:P32297

Role: Principal ACh-binding subunit.

beta4 subunit

Participant: Gene Product: CHRNB4

Gene Product:

CHRNB4UniProtKB:P30926

Family:

Representative Members: CHRNB4UniProtKB:P30926

Role: Complementary ACh-site subunit.

alpha5 subunit1 accessory subunit in the modeled pentamer

Participant: Gene Product: CHRNA5

Gene Product:

CHRNA5UniProtKB:P30532

Family:

Representative Members: CHRNA5UniProtKB:P30532

Role: Accessory subunit that speeds desensitisation.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

synaptic transmission, cholinergicGO:0007271

Locations

postsynaptic membraneGO:0045211

PMID:8663494

Cloned human alpha3/beta4 with or without alpha5 reaches the oocyte surface and yields functional receptors; alpha5 speeds desensitization.

alpha5 subunits coassembled very efficiently with alpha3beta2 or alpha3beta4 combinations.

PMID:10531434

Native mouse beta-subunit knockouts establish the importance of beta4-containing receptors in autonomic ganglia; this is not a direct human copy-number measurement.

Homomeric alpha7 nAChRProtein Complexnachr_alpha7

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

alpha7 nAChR ACh-gated cation channel

alpha7_nachr_channel

Participant: Protein Complex: human alpha7 homopentamer

Protein Complex:

human alpha7 homopentamerGO:0005892

Active units:

alpha7 subunit5

Participant: Gene Product: CHRNA7

Gene Product:

CHRNA7UniProtKB:P36544

Family:

CHRNA7 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA7UniProtKB:P36544

Role: Five identical subunits form the ligand-binding interfaces and central cation pore.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

acetylcholine receptor signaling pathwayGO:0095500

Locations

plasma membraneGO:0005886

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.

PMID:8906617

Human alpha7 alone forms a functional ACh-gated receptor.

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.

alpha9alpha10 nAChRProtein Complexnachr_alpha9alpha10

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

alpha9alpha10 nAChR ACh-gated cation channel

alpha9alpha10_nachr_channel

Participant: Protein Complex: alpha9alpha10 nicotinic receptor

Protein Complex:

alpha9alpha10 nicotinic receptorGO:0005892

Active units:

alpha9 subunit

Participant: Gene Product: CHRNA9

Gene Product:

CHRNA9UniProtKB:Q9UGM1

Family:

CHRNA9 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA9UniProtKB:Q9UGM1

Role: ACh-binding subunit; can form homomers in heterologous expression.

alpha10 subunit

Participant: Gene Product: CHRNA10

Gene Product:

CHRNA10UniProtKB:Q9GZZ6

Family:

CHRNA10 nicotinic receptor subunit lineagePANTHER:PTHR18945 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.

Representative Members: CHRNA10UniProtKB:Q9GZZ6

Role: Partner subunit required for the native heteromer.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

acetylcholine receptor signaling pathwayGO:0095500

PMID:11752216

Cloned human alpha9 and alpha10 form functional ACh-responsive receptors; the experiment grounds the human channel, while native hair-cell physiology requires separate evidence.

PMID:34867208

Review distinguishes receptor calcium entry from recruitment of the nearby SK2 potassium channel and net hair-cell inhibition.

secondary activation of a nearby calcium-dependent SK2 potassium channel

Muscarinic ACh receptor (GPCR) signallingSignaling Pathwaymuscarinic_reception

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.

G protein-coupled acetylcholine receptor signaling pathwayGO:0007213

Variant set: Muscarinic G protein coupling class by G protein family coupled (One Or More)

M1/M3/M5 -> Gq/11 -> PLC betaSignaling Pathwaymachr_gq_branch

phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathwayGO:0007207

Connections

machr_gq_activation -> machr_gq_plc_effector Positively Regulates

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.

PMID:8626481

Purified receptor/Gq/PLC-beta1 vesicle reconstitution requires agonist and GTP for PLC activation.

Both GTP and agonist were required for PLC activation

PMID:8508928

Human M1 expressed in CHO cells engages endogenous Gq and G11; these host G proteins are not represented as human construct measurements.

Part 1: receptor and Gq/11 activation

M1/M3/M5 activate G alpha q/11Regulatory Stepmachr_gq_activation

Part 1: M1/M3/M5 G protein-coupled ACh receptors

M1/M3/M5 G protein-coupled ACh receptorsRegulatory Stepm1_m3_m5_receptor

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 set: Named member alternatives by gene product (One Or More)

CHRM1m1_m3_m5_receptor_chrm1_implementation

Annotons

CHRM1 — M1/M3/M5 G protein-coupled ACh receptors

m1_m3_m5_receptor_chrm1

Participant: Gene Product: CHRM1 (M1)

Gene Product:

CHRM1 (M1)UniProtKB:P11229

Family:

CHRM1 lineagePANTHER:PTHR24247:SF182 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM1 (M1)UniProtKB:P11229

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathwayGO:0007207

Locations

plasma membraneGO:0005886

PMID:31073061

M1, M3 and M5 couple to Gq/11.

M1R, M3R, and M5R couple to the Gq/ 11 family

PMID:8508928

The human M1 receptor activates both Gq alpha and G11 alpha.

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.

CHRM3m1_m3_m5_receptor_chrm3_implementation

Annotons

CHRM3 — M1/M3/M5 G protein-coupled ACh receptors

m1_m3_m5_receptor_chrm3

Participant: Gene Product: CHRM3 (M3)

Gene Product:

CHRM3 (M3)UniProtKB:P20309

Family:

CHRM3 lineagePANTHER:PTHR24247:SF183 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM3 (M3)UniProtKB:P20309

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathwayGO:0007207

Locations

plasma membraneGO:0005886

PMID:31073061

M1, M3 and M5 couple to Gq/11.

M1R, M3R, and M5R couple to the Gq/ 11 family

PMID:8508928

The human M1 receptor activates both Gq alpha and G11 alpha.

CHRM5m1_m3_m5_receptor_chrm5_implementation

Annotons

CHRM5 — M1/M3/M5 G protein-coupled ACh receptors

m1_m3_m5_receptor_chrm5

Participant: Gene Product: CHRM5 (M5)

Gene Product:

CHRM5 (M5)UniProtKB:P08912

Family:

CHRM5 lineagePANTHER:PTHR24247:SF209 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM5 (M5)UniProtKB:P08912

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathwayGO:0007207

Locations

plasma membraneGO:0005886

PMID:31073061

M1, M3 and M5 couple to Gq/11.

M1R, M3R, and M5R couple to the Gq/ 11 family

PMID:8508928

The human M1 receptor activates both Gq alpha and G11 alpha.

Part 2: G alpha q/11 family switch

G alpha q/11 family switchRegulatory Stepg_alpha_q_11

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 set: Named member alternatives by gene product (One Or More)

GNAQg_alpha_q_11_gnaq_implementation

Annotons

GNAQ — G alpha q/11 family switch

g_alpha_q_11_gnaq

Participant: Gene Product: GNAQ

Gene Product:

GNAQUniProtKB:P50148

Family:

GNAQ lineagePANTHER:PTHR10218:SF329 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: GNAQUniProtKB:P50148

Function

G protein activityGO:0003925

Processes

phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathwayGO:0007207

Locations

plasma membraneGO:0005886

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.

PMID:31073061

The M1 receptor was solved in complex with G11.

Here, we present and compare the cryo-electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA

GNA11g_alpha_q_11_gna11_implementation

Annotons

GNA11 — G alpha q/11 family switch

g_alpha_q_11_gna11

Participant: Gene Product: GNA11

Gene Product:

GNA11UniProtKB:P29992

Family:

GNA11 lineagePANTHER:PTHR10218:SF328 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: GNA11UniProtKB:P29992

Function

G protein activityGO:0003925

Processes

phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathwayGO:0007207

Locations

plasma membraneGO:0005886

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.

PMID:31073061

The M1 receptor was solved in complex with G11.

Here, we present and compare the cryo-electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA

Part 2: PLC beta, IP3/calcium and DAG/PKC effector cascade

PLC beta hydrolysis of PIP2 (shared Gq effector)machr_gq_plc_effector

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.

Realized by module gpcr_plc_calcium_pkc_signaling#plc_beta_activation

M2/M4 Gi signaling and inhibitory cAMP outputSignaling Pathwaymachr_gi_branch

adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathwayGO:0007197

Connections

machr_gi_activation -> machr_gi_adenylyl_cyclase Negatively Regulates

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.

PMID:7961880

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.

PMID:17065363

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.

Part 1: receptor and Gi/o activation

M2/M4 activate G alpha i/oRegulatory Stepmachr_gi_activation

Part 1: M2/M4 G protein-coupled ACh receptors

M2/M4 G protein-coupled ACh receptorsRegulatory Stepm2_m4_receptor

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 set: Named member alternatives by gene product (One Or More)

CHRM2m2_m4_receptor_chrm2_implementation

Annotons

CHRM2 — M2/M4 G protein-coupled ACh receptors

m2_m4_receptor_chrm2

Participant: Gene Product: CHRM2 (M2)

Gene Product:

CHRM2 (M2)UniProtKB:P08172

Family:

CHRM2 lineagePANTHER:PTHR24247:SF207 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM2 (M2)UniProtKB:P08172

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathwayGO:0007197

Locations

plasma membraneGO:0005886

M2 slows the heart and, with M4, acts as the presynaptic autoreceptor that inhibits ACh release.

PMID:31073061

M2 and M4 couple to Gi/o.

whereas M2R and M4R couple to the Gi/ o family

PMID:19478075

Presynaptic M2/M4 autoreceptors restrain ACh release, and the restraint is pertussis-toxin (Gi/o) sensitive.

This reduction was fully corrected by pertussis toxin, atropine (a nonselective muscarinic antagonist), or methoctramine (a selective M2/M4 muscarinic receptor antagonist).

CHRM4m2_m4_receptor_chrm4_implementation

Annotons

CHRM4 — M2/M4 G protein-coupled ACh receptors

m2_m4_receptor_chrm4

Participant: Gene Product: CHRM4 (M4)

Gene Product:

CHRM4 (M4)UniProtKB:P08173

Family:

CHRM4 lineagePANTHER:PTHR24247:SF180 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM4 (M4)UniProtKB:P08173

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathwayGO:0007197

Locations

plasma membraneGO:0005886

M2 slows the heart and, with M4, acts as the presynaptic autoreceptor that inhibits ACh release.

PMID:31073061

M2 and M4 couple to Gi/o.

whereas M2R and M4R couple to the Gi/ o family

PMID:19478075

Presynaptic M2/M4 autoreceptors restrain ACh release, and the restraint is pertussis-toxin (Gi/o) sensitive.

This reduction was fully corrected by pertussis toxin, atropine (a nonselective muscarinic antagonist), or methoctramine (a selective M2/M4 muscarinic receptor antagonist).

Part 2: Gi alpha switches

Gi alpha switchesRegulatory Stepg_alpha_i_o

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 set: Named member alternatives by gene product (One Or More)

GNAI1g_alpha_i_o_gnai1_implementation

Annotons

GNAI1 — Gi alpha switches

g_alpha_i_o_gnai1

Participant: Gene Product: GNAI1

Gene Product:

GNAI1UniProtKB:P63096

Family:

GNAI1 lineagePANTHER:PTHR10218:SF359 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: GNAI1UniProtKB:P63096

Function

G protein activityGO:0003925

Processes

adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathwayGO:0007197

Locations

plasma membraneGO:0005886

PMID:11181437

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.

PMID:7961880

Transfected Gi2 mutants and M4 coupling affect a cAMP-dependent reporter; protein lipidation and assay context constrain interpretation.

GNAI2g_alpha_i_o_gnai2_implementation

Annotons

GNAI2 — Gi alpha switches

g_alpha_i_o_gnai2

Participant: Gene Product: GNAI2

Gene Product:

GNAI2UniProtKB:P04899

Family:

GNAI2 lineagePANTHER:PTHR10218:SF73 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: GNAI2UniProtKB:P04899

Function

G protein activityGO:0003925

Processes

adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathwayGO:0007197

Locations

plasma membraneGO:0005886

PMID:11181437

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.

PMID:7961880

Transfected Gi2 mutants and M4 coupling affect a cAMP-dependent reporter; protein lipidation and assay context constrain interpretation.

Part 2: inhibited adenylyl cyclase step (optional)

Adenylyl cyclase effector interfacemachr_gi_adenylyl_cyclase

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.

Realized by module gpcr_camp_pka_signaling#adenylyl_cyclase_activation

M2-Go receptionSignaling Pathwaymachr_go_branch

A receptor/G-protein reception alternative. Downstream ion-channel and cAMP mechanisms are not inferred from the structural complex alone.

Context

Homo sapiensNCBITaxon:9606

Annotons

M2 receptor coupled to Go

m2_go_receptor

Participant: Gene Product: CHRM2

Gene Product:

CHRM2UniProtKB:P08172

Family:

CHRM2 lineagePANTHER:PTHR24247:SF207 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.

Representative Members: CHRM2UniProtKB:P08172

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

G protein-coupled acetylcholine receptor signaling pathwayGO:0007213

Locations

plasma membraneGO:0005886

Human M2 receptor activation of Go; the structural preparation includes engineered receptor and stabilizing antibody components.

PMID:31073061

The M2-GoA complex resolves a human receptor/G-alpha pair without requiring a downstream adenylyl cyclase assertion.

Go alpha downstream of M2

m2_go_switch

Participant: Gene Product: GNAO1

Gene Product:

GNAO1UniProtKB:P09471

Family:

GNAO1 lineagePANTHER:PTHR10218:SF361 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.

Representative Members: GNAO1UniProtKB:P09471

Function

G protein activityGO:0003925

Processes

G protein-coupled acetylcholine receptor signaling pathwayGO:0007213

Locations

plasma membraneGO:0005886

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.

PMID:31073061

M2-GoA structural coupling is directly resolved; RCSB 6OIK identifies the Go entity as human P09471, while the mouse component is the antibody fragment.

PMID:7961880

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.

file:modules/acetylcholine_signaling-source-analysis/README.md

Retained RCSB entity metadata distinguish engineered human GoA from the mouse antibody component and document the human Gi1/G11 chimera in the M1 preparation.

Connections

m2_go_receptor -> m2_go_switch Positively Regulates

Activated M2 couples to the Go nucleotide switch.

PMID:31073061

Receptor-bound GoA structure directly supports this coupling; exact construct metadata are retained in the source analysis.

M1/M3-G14 experimental couplingSignaling Pathwaymachr_g14_branch

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

Homo sapiensNCBITaxon:9606

Annotons

G14 activation in the M1/M3 BRET system

g_alpha_14_context

Participant: Gene Product: GNA14

Gene Product:

GNA14UniProtKB:O95837

Family:

GNA14 exemplar within the G-alpha familyPANTHER:PTHR10218:SF213 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.

Representative Members: GNA14UniProtKB:O95837

Function

G protein activityGO:0003925

Processes

G protein-coupled acetylcholine receptor signaling pathwayGO:0007213

Locations

plasma membraneGO:0005886

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.

PMID:38671143

Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay.

file:human/GNA14/GNA14-source-analysis/README.md

Reproducible method/supplier provenance supports a human-construct inference while explicitly leaving actual assayed-sequence identity unresolved.

Connections

m1_m3_g14_receptor -> g_alpha_14_context Positively Regulates

Carbachol-bound M1/M3 activates G14 in the reported BRET expression system.

PMID:38671143

Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay.

Part 1: M1/M3 coupling to G14 in an expression assay

M1/M3 coupling to G14 in an expression assayRegulatory Stepm1_m3_g14_receptor

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 set: Named member alternatives by gene product (One Or More)

CHRM1m1_m3_g14_receptor_chrm1_implementation

Annotons

CHRM1 — M1/M3 coupling to G14 in an expression assay

m1_m3_g14_receptor_chrm1

Participant: Gene Product: CHRM1 (M1)

Gene Product:

CHRM1 (M1)UniProtKB:P11229

Family:

CHRM1 lineagePANTHER:PTHR24247:SF182 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM1 (M1)UniProtKB:P11229

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

G protein-coupled acetylcholine receptor signaling pathwayGO:0007213

Locations

plasma membraneGO:0005886

Carbachol activates G14 through M1/M3 in BRET experiments; ligand-dependent response magnitude and kinetics preclude universal coupling efficiency.

PMID:38671143

Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay.

CHRM3m1_m3_g14_receptor_chrm3_implementation

Annotons

CHRM3 — M1/M3 coupling to G14 in an expression assay

m1_m3_g14_receptor_chrm3

Participant: Gene Product: CHRM3 (M3)

Gene Product:

CHRM3 (M3)UniProtKB:P20309

Family:

CHRM3 lineagePANTHER:PTHR24247:SF183 Classification of the exact selected member; it does not allow substitution by another family member.

Representative Members: CHRM3 (M3)UniProtKB:P20309

Function

G protein-coupled acetylcholine receptor activityGO:0016907

Processes

G protein-coupled acetylcholine receptor signaling pathwayGO:0007213

Locations

plasma membraneGO:0005886

Carbachol activates G14 through M1/M3 in BRET experiments; ligand-dependent response magnitude and kinetics preclude universal coupling efficiency.

PMID:38671143

Full-text BRET results resolve G14 activation by carbachol-bound M1 and M3; this is receptor/G-protein activation, not a direct PLC assay.

Part 6: acetylcholine hydrolysis and signal termination

AChE hydrolysis of acetylcholine in the synaptic cleftReactionach_hydrolysis

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.

Context

Homo sapiensNCBITaxon:9606

Annotons

ACHE acetylcholinesterase activity

ache_hydrolysis

Participant: Gene Product: ACHE

Gene Product:

ACHEUniProtKB:P22303

Family:

ACHE lineagePANTHER:PTHR43918:SF11 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.

Representative Members: ACHEUniProtKB:P22303

Function

acetylcholinesterase activityGO:0003990

Substrates: acetylcholineCHEBI:15355

Products: cholineCHEBI:15354

Processes

acetylcholine catabolic process in synaptic cleftGO:0001507

Locations

synaptic cleftGO:0043083

Terminates both nicotinic and muscarinic signalling and returns choline for reuptake; it is the target of organophosphates and of therapeutic cholinesterase inhibitors.

PMID:10869390

AChE terminates transmission at cholinergic synapses.

Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses

PMID:10869390

AChE-null mice survive with delayed development, showing partial compensation by butyrylcholinesterase.

These findings indicate that butyrylcholinesterase and possibly other enzymes are capable of compensating for some functions of AChE

Part 7: muscarinic receptor desensitisation and G protein deactivation (optional)

GRK desensitisation of mAChRs and RGS acceleration of G alpha GTP hydrolysisRegulatory Stepach_muscarinic_termination

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

Homo sapiensNCBITaxon:9606

Variant set: Context-dependent regulatory mechanisms by regulator mechanism (One Or More)

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.

GRK2 phosphorylation of muscarinic receptorsgrk2_machr_regulatory_mechanism

Annotons

GRK2 phosphorylation of muscarinic receptors

grk2_machr

Participant: Gene Product: GRK2 (beta-ARK1, Adrbk1)

Gene Product:

GRK2 (beta-ARK1, Adrbk1)UniProtKB:P25098

Family:

GRK2 (beta-ARK1, Adrbk1) lineagePANTHER:PTHR24355:SF22 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.

Representative Members: GRK2 (beta-ARK1, Adrbk1)UniProtKB:P25098

Function

G protein-coupled receptor kinase activityGO:0004703

Targets: CHRM2UniProtKB:P08172

Processes

desensitization of G protein-coupled receptor signaling pathwayGO:0002029

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.

PMID:8798423

Purified human M2 is phosphorylated by GRK2 in an agonist- and charged-phospholipid-dependent preparation. The abstract does not specify the kinase species.

charged phospholipids are required for agonist-dependent phosphorylation of receptors by GRK2.

PMID:9495886

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.

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

GRK5 M2 phosphorylation and muscarinic desensitizationgrk5_autoreceptor_regulatory_mechanism

Annotons

GRK5 M2 phosphorylation and muscarinic desensitization

grk5_autoreceptor

Participant: Gene Product: GRK5

Gene Product:

GRK5UniProtKB:P34947

Family:

GRK5 lineagePANTHER:PTHR24355:SF27 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.

Representative Members: GRK5UniProtKB:P34947

Function

G protein-coupled receptor kinase activityGO:0004703

Targets: CHRM2UniProtKB:P08172

Processes

desensitization of G protein-coupled receptor signaling pathwayGO:0002029

Locations

presynapseGO:0098793

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.

PMID:8288567

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.

GRK5 phosphorylates the beta 2-adrenergic receptor (beta 2AR), m2 muscarinic cholinergic receptor, and rhodopsin in an agonist-dependent manner

PMID:19478075

GRK5 loss selectively impairs M2/M4 (not M1) internalisation and reduces ACh release.

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.

PMID:9495886

GRK5 facilitates sequestration of M2 but not M3 receptors.

coexpression of GRK4 delta, GRK5, but not GRK6, in BHK-21 cells facilitated sequestration of m2, but not m3, receptors.

RGS2 GTPase-activating activity on G alpha qrgs2_gq_gap_regulatory_mechanism

Annotons

RGS2 GTPase-activating activity on G alpha q

rgs2_gq_gap

Participant: Gene Product: RGS2

Gene Product:

RGS2UniProtKB:P41220

Family:

RGS2 lineagePANTHER:PTHR10845:SF43 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.

Representative Members: RGS2UniProtKB:P41220

Function

GTPase activator activityGO:0005096

Targets: GNAQUniProtKB:P50148

Terminates the Gq branch (RGD: Rgs2 on the Gq proteins downstream of M3).

PMID:19478087

RGS2 is a potent and selective GAP for G alpha q.

RGS2 is unique in its in vitro potency and selectivity as a GAP for Galpha(q) subunits.

RGS4 GAP activity on Girgs4_gi_gap_regulatory_mechanism

Annotons

RGS4 GAP activity on Gi

rgs4_gi_gap

Participant: Gene Product: RGS4

Gene Product:

RGS4UniProtKB:P49798

Family:

RGS4 lineagePANTHER:PTHR10845:SF184 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.

Representative Members: RGS4UniProtKB:P49798

Function

GTPase activator activityGO:0005096

Targets: GNAI1UniProtKB:P63096

RGS4 accelerates Gi-family GTP hydrolysis. Native cardiac effects are not assumed interchangeable with the RGS6-Gbeta5 complex.

PMID:8756726

RGS4 accelerates GTP hydrolysis by Gi alpha subunits.

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.

PMID:8756726

Gs alpha is not a substrate, giving Gi-family selectivity.

All Gi subfamily members assayed were substrates for these GAPs; Gs alpha was not.

RGS6–GNB5 GAP complexhuman_rgs6_gnb5_gap_regulatory_mechanism

Annotons

RGS6–GNB5 GAP complex

human_rgs6_gnb5_gap

Participant: Protein Complex: RGS6–GNB5 complex

Protein Complex:

RGS6–GNB5 complexGO:1902773

Active units:

RGS6 catalytic GAP component

Participant: Gene Product: RGS6

Gene Product:

RGS6UniProtKB:P49758

Family:

RGS6 lineagePANTHER:PTHR45746:SF2 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.

Representative Members: RGS6UniProtKB:P49758

Role: RGS domain accelerates G-alpha GTP hydrolysis; it does not hydrolyze GTP as its own substrate.

GNB5 partner

Participant: Gene Product: GNB5

Gene Product:

GNB5UniProtKB:O14775

Family:

GNB5 lineagePANTHER:PTHR19850 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.

Representative Members: GNB5UniProtKB:O14775

Role: GGL-binding partner required for stable native R7 complex expression and function in the sampled cardiac context.

Function

GTPase activator activityGO:0005096

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.

PMID:10521509

Purified RGS6/Gbeta5 complexes accelerate Go GTP hydrolysis; their biochemical target is not inferred from RGS4.

PMID:20884879

Native mouse loss of either partner prolongs muscarinic potassium-current deactivation; partner association supports Rgs6 expression/stability.

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.

Part 8: comparative hair-cell receptor capacity (optional)

Rat alpha9/alpha10 receptor comparatorProtein Complexrat_hair_cell_receptor

Context

Rattus norvegicusNCBITaxon:10116

Annotons

Rat alpha9/alpha10 receptor comparator cation-channel activity

rat_hair_cell_receptor_channel

Participant: Protein Complex: Rat alpha9/alpha10 receptor comparator

Protein Complex:

Rat alpha9/alpha10 receptor comparatorGO:0005892

Active units:

Chrna9 subunit

Participant: Gene Product: Chrna9

Gene Product:

Chrna9UniProtKB:P43144

Family:

Chrna9 nicotinic receptor subunit lineagePANTHER:PTHR18945 Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted.

Representative Members: Chrna9UniProtKB:P43144

Role: ACh-binding subunit; can form homomers in heterologous expression.

Chrna10 subunit

Participant: Gene Product: Chrna10

Gene Product:

Chrna10UniProtKB:Q9JLB5

Family:

Chrna10 nicotinic receptor subunit lineagePANTHER:PTHR18945 Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted.

Representative Members: Chrna10UniProtKB:Q9JLB5

Role: Partner subunit required for the native heteromer.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

acetylcholine receptor signaling pathwayGO:0095500

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.

PMID:22371598

recombinant and native chicken α9α10 receptors

PMID:34867208

Review interprets the taxon-dependent channel properties and distinction between calcium entry and net hair-cell inhibition.

Part 9: comparative hair-cell receptor capacity (optional)

Chicken alpha9/alpha10 receptor comparatorProtein Complexchicken_hair_cell_receptor

Context

Gallus gallusNCBITaxon:9031

Annotons

Chicken alpha9/alpha10 receptor comparator cation-channel activity

chicken_hair_cell_receptor_channel

Participant: Protein Complex: Chicken alpha9/alpha10 receptor comparator

Protein Complex:

Chicken alpha9/alpha10 receptor comparatorGO:0005892

Active units:

CHRNA9 subunit

Participant: Gene Product: CHRNA9

Gene Product:

CHRNA9UniProtKB:Q9PTS8

Family:

CHRNA9 nicotinic receptor subunit lineagePANTHER:PTHR18945 Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted.

Representative Members: CHRNA9UniProtKB:Q9PTS8

Role: ACh-binding subunit; can form homomers in heterologous expression.

CHRNA10 subunit

Participant: Gene Product: CHRNA10

Gene Product:

CHRNA10UniProtKB:Q9I8C7

Family:

CHRNA10 nicotinic receptor subunit lineagePANTHER:PTHR18945 Exact subunit exemplar in a broader ligand-gated channel family; family-wide ACh specificity or replacement of another subunit is not asserted.

Representative Members: CHRNA10UniProtKB:Q9I8C7

Role: Partner subunit required for the native heteromer.

Function

acetylcholine-gated monoatomic cation-selective channel activityGO:0022848

Processes

acetylcholine receptor signaling pathwayGO:0095500

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.

PMID:22371598

recombinant and native chicken α9α10 receptors

PMID:34867208

Review interprets the taxon-dependent channel properties and distinction between calcium entry and net hair-cell inhibition.

Part 10: native mouse cardiac regulatory comparison (optional)

Mouse Rgs6–Gnb5 regulation of cardiac M2 signalingRegulatory Stepmouse_cardiac_regulation

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.

Context

Mus musculusNCBITaxon:10090

Connections

mouse_rgs6_regulation -> mouse_m2_signal Negatively Regulates

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.

PMID:20884879

Deletion of either partner prolongs deactivation in native mouse atrial cells; the Rgs6 phenotype also occurs in sinoatrial cells.

PMID:24318880

Native mouse comparison finds enhanced parasympathetic influence after RGS6 ablation, not RGS4 ablation.

RGS6 ablation enhances parasympathetic influence on the heart; RGS4 ablation does not.

Part 1: M2-driven cardiac signaling

M2-initiated cardiac responsemouse_m2_signal

Annotons

Mouse M2 muscarinic receptor

mouse_m2_receptor

Participant: Gene Product: Chrm2

Gene Product:

Chrm2UniProtKB:Q9ERZ4

Family:

Chrm2 lineagePANTHER:PTHR24247:SF207 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.

Representative Members: Chrm2UniProtKB:Q9ERZ4

Function

G protein-coupled acetylcholine receptor activityGO:0016907

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.

PMID:20884879

Native mouse atrial and sinoatrial cells show carbachol-evoked muscarinic currents with prolonged deactivation after Rgs6 or Gnb5 loss.

Part 2: Rgs6-Gnb5 temporal regulation

Rgs6-Gnb5 GAP complexmouse_rgs6_regulation

Annotons

Rgs6–Gnb5 GAP complex

mouse_rgs6_gnb5_gap

Participant: Protein Complex: Rgs6–Gnb5 complex

Protein Complex:

Rgs6–Gnb5 complexGO:1902773

Active units:

Rgs6 catalytic GAP component

Participant: Gene Product: Rgs6

Gene Product:

Rgs6UniProtKB:Q9Z2H2

Family:

Rgs6 lineagePANTHER:PTHR45746:SF2 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.

Representative Members: Rgs6UniProtKB:Q9Z2H2

Role: RGS domain accelerates G-alpha GTP hydrolysis; it does not hydrolyze GTP as its own substrate.

Gnb5 partner

Participant: Gene Product: Gnb5

Gene Product:

Gnb5UniProtKB:P62881

Family:

Gnb5 lineagePANTHER:PTHR19850 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.

Representative Members: Gnb5UniProtKB:P62881

Role: GGL-binding partner required for stable native R7 complex expression and function in the sampled cardiac context.

Function

GTPase activator activityGO:0005096

PMID:10521509

Purified RGS6/Gbeta5 complexes accelerate Go GTP hydrolysis; their biochemical target is not inferred from RGS4.

PMID:20884879

Native mouse loss of either partner prolongs muscarinic potassium-current deactivation; partner association supports Rgs6 expression/stability.