CHRNA3

Summary: Refine the broad receptor/channel activity to the independently represented acetylcholine-gated cation-channel activity.

Reason: The subunit contributes to the assembled pentamer rather than enabling a complete channel alone. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine-gated monoatomic cation-selective channel activity

Summary: Refine the broad receptor/channel activity to the independently represented acetylcholine-gated cation-channel activity.

Reason: The subunit contributes to the assembled pentamer rather than enabling a complete channel alone. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine-gated monoatomic cation-selective channel activity

Summary: Refine the broad receptor/channel activity to the independently represented acetylcholine-gated cation-channel activity.

Reason: The subunit contributes to the assembled pentamer rather than enabling a complete channel alone. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine-gated monoatomic cation-selective channel activity

Summary: Remove the uninformative bare protein-binding term under the project policy, not the reported positive interaction.

Reason: UBXN2A/VCP/CHIP association concerns alpha3 folding and degradation as a client; it does not make alpha3 an E3 ligase or ERAD catalyst. Seeded partner identities are UniProtKB:P55072, UniProtKB:P68543, UniProtKB:Q9UNE7.

Summary: Remove the uninformative bare protein-binding term under the project policy, not the reported positive interaction.

Reason: LYPD6 affinity isolation from human brain captures receptor subunits/complexes; this does not establish a binary contact or identical functional inhibition for every captured subtype. Seeded partner identities are UniProtKB:Q86Y78.

Summary: Retain the organelle-level biosynthetic/ERAD pool of alpha3 as a non-core location.

Reason: The target ERAD/maturation study and curated rat-to-human trafficking inference concern receptor assembly before surface delivery. Plasma-membrane function does not exclude endoplasmic reticulum or Golgi localization; do not replace a valid root organelle with a subcompartment. ORGANELLES ER check (2026-11-05): UniProt's ER location is by similarity to rat P04757, whose ER row is an EXP from Rezvani et al. 2009 (PMID:19474315; abstract only here), where UBXD4 sits in ER and cis-Golgi and controls the distribution of alpha3 receptors between intracellular compartments and the surface. PMID:26265139 (full text) shows p97/CHIP-dependent ERAD of the alpha3 subunit in differentiated PC12 cells, a pool that is extracted from the ER. That is direct evidence of a biosynthetic and quality-control ER pool on the gene (as for ABCA4 and BACE2 in ER batch 1), so the row stays, but as KEEP_AS_NON_CORE rather than ACCEPT: the channel acts at the plasma and synaptic membrane, not in the ER. MARK_AS_OVER_ANNOTATED was the alternative, since no alpha3 staining with an ER marker is quoted, but the ERAD data place the subunit in the ER. A multi-pass subunit passing through the ER gets no NEW ER membrane row: that would claim residence. Neither source has an isoform restriction.

Summary: Retain the organelle-level biosynthetic/ERAD pool of alpha3 as a non-core location.

Reason: The target ERAD/maturation study and curated rat-to-human trafficking inference concern receptor assembly before surface delivery. Plasma-membrane function does not exclude endoplasmic reticulum or Golgi localization; do not replace a valid root organelle with a subcompartment. ORGANELLES ER check (2026-11-05): UniProt's ER location is by similarity to rat P04757, whose ER row is an EXP from Rezvani et al. 2009 (PMID:19474315; abstract only here), where UBXD4 sits in ER and cis-Golgi and controls the distribution of alpha3 receptors between intracellular compartments and the surface. PMID:26265139 (full text) shows p97/CHIP-dependent ERAD of the alpha3 subunit in differentiated PC12 cells, a pool that is extracted from the ER. That is direct evidence of a biosynthetic and quality-control ER pool on the gene (as for ABCA4 and BACE2 in ER batch 1), so the row stays, but as KEEP_AS_NON_CORE rather than ACCEPT: the channel acts at the plasma and synaptic membrane, not in the ER. MARK_AS_OVER_ANNOTATED was the alternative, since no alpha3 staining with an ER marker is quoted, but the ERAD data place the subunit in the ER. A multi-pass subunit passing through the ER gets no NEW ER membrane row: that would claim residence. Neither source has an isoform restriction.

Summary: Retain the organelle-level biosynthetic/trafficking pool of alpha3.

Reason: The target ERAD/maturation study and curated rat-to-human trafficking inference concern receptor assembly before surface delivery. Plasma-membrane function does not exclude endoplasmic reticulum or Golgi localization; do not replace a valid root organelle with a subcompartment.

Summary: Retain the organelle-level biosynthetic/trafficking pool of alpha3.

Reason: The target ERAD/maturation study and curated rat-to-human trafficking inference concern receptor assembly before surface delivery. Plasma-membrane function does not exclude endoplasmic reticulum or Golgi localization; do not replace a valid root organelle with a subcompartment.

Summary: Retain functional receptor surface localization.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: GO_REF:0000052. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: PMID:31708116. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: GO_REF:0000044. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: Reactome:R-HSA-622325. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: Reactome:R-HSA-622326. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: Reactome:R-HSA-629588. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: Reactome:R-HSA-629595. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: Reactome:R-HSA-629596. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain functional receptor surface localization.

Reason: Original source: Reactome:R-HSA-629599. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: PMID:11118490. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: PMID:20881005. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: PMID:31488329. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: GO_REF:0000117. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain membership in an acetylcholine-gated pentamer.

Reason: Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Functional human receptor currents support cation transmembrane transport.

Reason: This refines the broad ion-transport assertion without implying cation selectivity of an isolated subunit or identical permeability in every assembly. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Functional human receptor currents support cation transmembrane transport.

Reason: This refines the broad ion-transport assertion without implying cation selectivity of an isolated subunit or identical permeability in every assembly. Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Retain the PAINT-supported calcium-transport contribution of a cation-permeable neuronal receptor.

Reason: Calcium permeability depends on subunit combination; human alpha5 and alpha6 complex measurements provide specific examples, not an assertion that this isolated subunit is a calcium-selective channel. For alpha2, the target current assay establishes receptor function while the conserved permeability inference is retained without inventing an alpha2-specific calcium-flux experiment.

Summary: Mouse alpha3-null ganglia and bladder-strip experiments in PMID:10318955 show that alpha3-mediated autonomic transmission regulates smooth-muscle contraction; carbachol/electrical muscle responses distinguish the neural deficit from muscle contractile machinery.

Reason: Human CHRNA3 loss-of-function bladder disease in PMID:31708116 independently supports transfer of this physiological role.

Summary: The specific signaling mechanism is acetylcholine-dependent pore gating.

Reason: Refine the generic signaling term to the existing acetylcholine receptor signaling pathway, at complex level. Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine receptor signaling pathway

Summary: Retain the receptor-mediated receiver step of cholinergic transmission.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain the receptor-mediated receiver step of cholinergic transmission.

Reason: Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: The PAINT assertion traces to PTN000436077.

Reason: Human functional assembly supports a neuronal cholinergic receptor, but does not establish participation at a neuron-to-muscle synapse. Autonomic ganglion transmission upstream of muscle contraction is not itself that synapse. The historical IBD evidence and any target-specific neuromuscular pool remain unresolved; neither a short donor list nor lack of a muscle assay establishes evolutionary loss.

Summary: PMID:11450844 describes human gene characterization/variants and summarizes mouse autonomic phenotypes; the accessible abstract does not resolve a distinct alpha3-performed nervous-system developmental step.

Reason: Human CAKUT is secondary to impaired innervation/function and does not by itself establish this broad developmental mechanism. Preserve the experimental assertion pending full source adjudication, rather than infer a wrong-gene annotation.

Summary: The mouse donor experiment PMID:15275829 explicitly tests nicotine-induced hypolocomotion and finds altered responses in alpha3 heterozygotes.

Reason: Retain a contextual mammalian locomotor-response inference, not constitutive control of all movement or a direct human behavioral assay.

Summary: Mouse alpha3-null sympathetic ganglia in PMID:16162937 have reduced presynaptic acetylcholine release/high-affinity choline transport despite morphologically recognizable synapses.

Reason: The receptor participates through postsynaptic activity-dependent retrograde regulation; this does not locate alpha3 on the releasing terminal or give it choline-transporter activity. Human transfer is physiological inference.

Summary: Refine the broad receptor/channel activity to the independently represented acetylcholine-gated cation-channel activity.

Reason: The subunit contributes to the assembled pentamer rather than enabling a complete channel alone. Original source: PMID:20438829. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine-gated monoatomic cation-selective channel activity

Summary: Refine the broad receptor/channel activity to the independently represented acetylcholine-gated cation-channel activity.

Reason: The subunit contributes to the assembled pentamer rather than enabling a complete channel alone. Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine-gated monoatomic cation-selective channel activity

Summary: Refine the broad receptor/channel activity to the independently represented acetylcholine-gated cation-channel activity.

Reason: The subunit contributes to the assembled pentamer rather than enabling a complete channel alone. Original source: GO_REF:0000117. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: acetylcholine-gated monoatomic cation-selective channel activity

Summary: Functional surface expression of human receptors resolves the broad membrane/periphery assertion to plasma membrane.

Reason: This does not deny intracellular assembly or trafficking pools. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: plasma membrane

Summary: Functional surface expression of human receptors resolves the broad membrane/periphery assertion to plasma membrane.

Reason: This does not deny intracellular assembly or trafficking pools. Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: plasma membrane

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: PMID:11118490. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: PMID:20881005. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: PMID:31488329. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain contribution to acetylcholine-gated cation conductance.

Reason: Original source: PMID:20438829. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: The rat alpha3 source PMID:11297818 supports subtype-specific antibody/function analysis in superior cervical ganglion neurons, but the available abstract does not resolve the exact dendrite protein-localization image behind the transfer.

Reason: This specific subcellular pool is unresolved; neuronal expression and surface current alone do not adjudicate it.

Summary: PMID:21659607 tests mouse hypothalamic alpha3beta4-containing receptors and POMC-dependent feeding suppression.

Reason: Retain the conserved, context-dependent receptor contribution to appetite regulation, explicitly distinguishing mouse circuit evidence from direct human behavior and from autonomous hormone activity.

Summary: Functional human receptor currents support cation transmembrane transport.

Reason: This refines the broad ion-transport assertion without implying cation selectivity of an isolated subunit or identical permeability in every assembly. Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Functional human receptor currents support cation transmembrane transport.

Reason: This refines the broad ion-transport assertion without implying cation selectivity of an isolated subunit or identical permeability in every assembly. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Retain receptor response to nicotine.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: The human smoking-association study PMID:18227835 and functional receptor study PMID:20881005 establish risk association and molecular nicotine responses, respectively.

Reason: The latter measures currents, permeability and desensitization, not behavior. The specific human behavioral consequence is not independently resolved here; preserve the original assertion without equating an association or recombinant current with an observed behavioral mechanism.

Summary: Retain contribution to the intersubunit acetylcholine recognition site.

Reason: Original source: PMID:8906617. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: The measured alpha3-containing ganglionic receptor current regulates the postsynaptic membrane potential; refine the broader potential regulation to that supported compartment..

Reason: The measured alpha3-containing ganglionic receptor current regulates the postsynaptic membrane potential; refine the broader potential regulation to that supported compartment.

Proposed replacements: regulation of postsynaptic membrane potential

Summary: The rat synaptosomal study PMID:12065717 infers a possible alpha3/alpha6beta2beta3 composition from pharmacology, without uniquely assigning the alpha3 chain; mouse PMID:16162937 demonstrates a postsynaptic alpha3-dependent retrograde effect on acetylcholine release.

Reason: These do not settle the specific human alpha3 presynaptic pool. The claim remains unresolved, not contradicted by its ganglionic role.

Summary: The rat alpha3 source PMID:11297818 supports subtype-specific antibody/function analysis in superior cervical ganglion neurons, but the available abstract does not resolve the exact neuronal cell body protein-localization image behind the transfer.

Reason: This specific subcellular pool is unresolved; neuronal expression and surface current alone do not adjudicate it.

Summary: PMID:21540349 tests cholesterol/sphingomyelin manipulation and alpha3beta2 currents in rat hippocampal neurons.

Reason: Lipid-dependent channel function does not uniquely identify stable raft partitioning of human alpha3. Preserve the inferred microdomain claim pending target-resolved localization, without denying lipid modulation.

Summary: Refine the broad synaptic location to the supported receptor membrane pool(s).

Reason: Retain synaptic receptor localization. Molecular surface currents directly support gating; specialized native synaptic positions are conserved biological inferences, not images from the recombinant expression assay. Original source: PMID:21659607. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific. Refine the broad location to postsynaptic membrane, the specific synaptic pool independently supported here. This is not an inference of a native compartment from an oocyte current alone.

Proposed replacements: postsynaptic membrane

Summary: Refine the broad synaptic location to the supported receptor membrane pool(s).

Reason: Retain synaptic receptor localization. Molecular surface currents directly support gating; specialized native synaptic positions are conserved biological inferences, not images from the recombinant expression assay. Original source: PMID:11118490. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific. Refine the broad location to postsynaptic membrane, the specific synaptic pool independently supported here. This is not an inference of a native compartment from an oocyte current alone.

Proposed replacements: postsynaptic membrane

Summary: Retain a conserved postsynaptic receptor pool.

Reason: Molecular surface currents directly support gating; specialized native synaptic positions are conserved biological inferences, not images from the recombinant expression assay. Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain a conserved postsynaptic receptor pool.

Reason: Molecular surface currents directly support gating; specialized native synaptic positions are conserved biological inferences, not images from the recombinant expression assay. Original source: GO_REF:0000002. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: The mouse alpha3-null retinal study PMID:11027228 reports delayed individual ganglion-cell dendritic refinement during altered cholinergic waves, with gross retinal organization preserved.

Reason: This supports a contextual activity-dependent developmental contribution, not an indispensable morphogenetic enzyme or direct human dendrite assay.

Summary: Retain depolarization from the inward cation current.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain an excitatory postsynaptic cation current.

Reason: Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain a mammalian autonomic receptor contribution to micturition.

Reason: PMID:11450844 explicitly distinguishes alpha3-null and beta2/beta4 double-null severe bladder phenotypes from beta4-only loss of nicotine-induced bladder-strip contraction; it is not evidence that every single subunit loss produces megacystis. PMID:10318955 resolves the ganglionic mechanism, and PMID:31708116 establishes human alpha3-associated bladder dysfunction. Beta4 transfer remains the conserved ganglionic partner inference, not a reported human beta4 disease in those families.

Summary: Retain a mammalian autonomic receptor contribution to micturition.

Reason: PMID:11450844 explicitly distinguishes alpha3-null and beta2/beta4 double-null severe bladder phenotypes from beta4-only loss of nicotine-induced bladder-strip contraction; it is not evidence that every single subunit loss produces megacystis. PMID:10318955 resolves the ganglionic mechanism, and PMID:31708116 establishes human alpha3-associated bladder dysfunction. Beta4 transfer remains the conserved ganglionic partner inference, not a reported human beta4 disease in those families.

Summary: Retain acetylcholine recognition coupled to channel gating.

Reason: Original source: GO_REF:0000033. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain acetylcholine recognition coupled to channel gating.

Reason: Original source: PMID:11118490. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain acetylcholine recognition coupled to channel gating.

Reason: Original source: PMID:20881005. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain acetylcholine recognition coupled to channel gating.

Reason: Original source: PMID:21659607. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain acetylcholine recognition coupled to channel gating.

Reason: Original source: GO_REF:0000117. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Retain acetylcholine recognition coupled to channel gating.

Reason: Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.

Summary: Refine the broad synaptic location to the supported receptor membrane pool(s).

Reason: Retain synaptic membrane localization. Molecular surface currents directly support gating; specialized native synaptic positions are conserved biological inferences, not images from the recombinant expression assay. Original source: GO_REF:0000044. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific. Refine the broad location to postsynaptic membrane, the specific synaptic pool independently supported here. This is not an inference of a native compartment from an oocyte current alone.

Proposed replacements: postsynaptic membrane

Summary: Refine the broad synaptic location to the supported receptor membrane pool(s).

Reason: Retain synaptic membrane localization. Molecular surface currents directly support gating; specialized native synaptic positions are conserved biological inferences, not images from the recombinant expression assay. Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific. Refine the broad location to postsynaptic membrane, the specific synaptic pool independently supported here. This is not an inference of a native compartment from an oocyte current alone.

Proposed replacements: postsynaptic membrane

Summary: The rat synaptosomal study PMID:12065717 infers a possible alpha3/alpha6beta2beta3 composition from pharmacology, without uniquely assigning the alpha3 chain; mouse PMID:16162937 demonstrates a postsynaptic alpha3-dependent retrograde effect on acetylcholine release.

Reason: These do not settle the specific human alpha3 presynaptic pool. The claim remains unresolved, not contradicted by its ganglionic role.

Summary: Retain the receptor response to acetylcholine.

Reason: Original source: GO_REF:0000024. Human alpha3 contributes principal ligand-binding faces to heteromeric ganglionic receptors with beta4 or beta2, sometimes including accessory alpha5 or beta3. Reconstituted alpha3beta4 and alpha3beta4beta3 stoichiometries are context-specific.