CHRNA4

Summary: Retain the ortholog-supported neuronal excitability context.

Reason: The exact mouse O70174 donor has an IMP assertion from PMID:10235262; its authentic abstract reports loss of nicotine responses in raphe magnus/thalamic neurons after alpha4 disruption. This supports neuronal excitability but does not make alpha4 a voltage-gated channel executing every phase of an action potential. Retain the existing broad process non-core; the defining performed work is ligand-gated cation conductance.

Summary: Retain the measured alpha4 response to hypoxia.

Reason: Full PMID:12189247 Results explicitly report alpha4 and beta2 endothelial receptor expression changing similarly to alpha7 under nicotine/hypoxia, with the alpha4/beta2 observations stated as data not shown. The paper’s causal angiogenesis experiments chiefly concern alpha7. Retain the alpha4 expression-response assertion without transferring that angiogenic mechanism.

Summary: Specify the acetylcholine-gated cation-channel activity.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The official broad receptor/channel terms can be refined to GO:0022848; GO:0015464 explicitly directs nicotinic ion channels to that term. Original evidence, qualifier and family/orthology sources remain unchanged.

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

Summary: Specify the acetylcholine-gated cation-channel activity.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The official broad receptor/channel terms can be refined to GO:0022848; GO:0015464 explicitly directs nicotinic ion channels to that term. Original evidence, qualifier and family/orthology sources remain unchanged.

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

Summary: Specify the acetylcholine-gated cation-channel activity.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The official broad receptor/channel terms can be refined to GO:0022848; GO:0015464 explicitly directs nicotinic ion channels to that term. Original evidence, qualifier and family/orthology sources remain unchanged.

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

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: Exact IntAct records join human CHRNA4 to Q6UXH1-1: yeast complementation tests alpha4 loop 331–600 and 331–381, and an in-vitro GST-loop pull-down uses radiolabeled CRELD2. The authentic PMID:16238698 abstract independently reports both CRELD2 forms binding alpha4. Preserve the positive engineered capability and exact product; full original Methods remain unavailable and these assays do not by themselves establish a native membrane-topology encounter or a separate receptor catalytic function. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: Exact IntAct records join human CHRNA4 to Q6UXH1-3: yeast complementation tests alpha4 loop 331–600 and 331–381, and an in-vitro GST-loop pull-down uses radiolabeled CRELD2. The authentic PMID:16238698 abstract independently reports both CRELD2 forms binding alpha4. Preserve the positive engineered capability and exact product; full original Methods remain unavailable and these assays do not by themselves establish a native membrane-topology encounter or a separate receptor catalytic function. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: Actual PMID:27344019 Methods/Results use recombinant human GST-LYPD6 affinity capture from human temporal-cortex extracts, with alpha4 detected among recovered nicotinic receptor subunits. This supports association with an alpha4-containing receptor complex; it does not isolate a binary alpha4 interface. PC12 alpha3beta4 and hippocampal/alpha7 functional experiments are not all transferred to alpha4. The absent exact IntAct join is not a negative assay. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: PMID:32814053 has three exact positive human-participant IntAct records for CHRNA4–APP/P05067: array, pooling and validated yeast two-hybrid assays. The APP participant carries a curated 670–671 mutation feature; this is not silently described as wild-type APP. General DULIP validation in the full article is not proof of a CHRNA4-specific mammalian validation. These six screen pairs have the same native-evidence limit. No better informative partner-class term was established for this exact tested product in this review. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Specify the measured translation-initiation-factor binding capability.

Reason: PMID:32814053 records the human CHRNA4–EIF2S2 pair in array, pooling and validated yeast two-hybrid assays (IntAct EBI-25838471, EBI-25995225 and EBI-26149372). The paper excludes reporter-autoactivating baits and retests pooled candidates pairwise; its general DULIP validation does not establish mammalian validation of this particular pair. EIF2S2/P20042 is the beta subunit of translation initiation factor eIF2, so the measured association fits the binding definition of GO:0031369. The other screen pairs share the same native-context uncertainty, but their tested partners do not establish this class. This refinement states assay-supported binding capability, not CHRNA4 translation regulation or a demonstrated encounter with EIF2S2 in native neurons.

Proposed replacements: translation initiation factor binding

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: PMID:32814053 has three exact positive human-participant IntAct records for CHRNA4–CBX1/P83916: array, pooling and validated yeast two-hybrid assays. The verified partner is a heterochromatin protein; its chromatin-binding activity is not transferred to CHRNA4. General DULIP validation in the full article is not proof of a CHRNA4-specific mammalian validation. These six screen pairs have the same native-evidence limit. No better informative partner-class term was established for this exact tested product in this review. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: PMID:32814053 has three exact positive human-participant IntAct records for CHRNA4–ADAMTSL4/Q6UY14-3: array, pooling and validated yeast two-hybrid assays. The exact ADAMTSL4 product record includes a 674–1097 sufficient-binding fragment; no extracellular-matrix mechanism is inferred. General DULIP validation in the full article is not proof of a CHRNA4-specific mammalian validation. These six screen pairs have the same native-evidence limit. No better informative partner-class term was established for this exact tested product in this review. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: PMID:32814053 has three exact positive human-participant IntAct records for CHRNA4–SORL1/Q92673: array, pooling and validated yeast two-hybrid assays. The verified partner is the sorting receptor SORL1; receptor trafficking by CHRNA4 is not established. General DULIP validation in the full article is not proof of a CHRNA4-specific mammalian validation. These six screen pairs have the same native-evidence limit. No better informative partner-class term was established for this exact tested product in this review. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Remove the uninformative bare-binding term while retaining exact interaction evidence.

Reason: PMID:32814053 has three exact positive human-participant IntAct records for CHRNA4–LRP1B/Q9NZR2: array, pooling and validated yeast two-hybrid assays. The verified partner is LRP1B; no endogenous lipoprotein-uptake role of CHRNA4 is inferred. General DULIP validation in the full article is not proof of a CHRNA4-specific mammalian validation. These six screen pairs have the same native-evidence limit. No better informative partner-class term was established for this exact tested product in this review. Current protein-binding policy supersedes the earlier non-core retention: remove only GO:0005515. The described positive interaction, product identity and assay limits remain evidence; this action does not assert that the interaction is false or transfer the partner's function onto the receptor subunit.

Summary: Retain the plasma-membrane receptor location.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Recombinant human surface receptor electrophysiology corroborates the source compartment.

Summary: Retain the plasma-membrane receptor location.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Recombinant human surface receptor electrophysiology corroborates the source compartment. The original mouse/Ensembl and subcellular mapping is preserved; current corroboration is not a reconstruction of the historical transfer.

Summary: Retain the plasma-membrane receptor location.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Recombinant human surface receptor electrophysiology corroborates the source compartment. The original mouse/Ensembl and subcellular mapping is preserved; current corroboration is not a reconstruction of the historical transfer.

Summary: Retain the explicitly represented plasma-membrane location.

Reason: Official Reactome:R-HSA-622325 was followed through its receptor/catalyst entities to human P43681 entity 507836, with plasma-membrane compartment. The highly sodium-permeable set explicitly contains the alpha4(2)-beta2(3) assembly. This source assertion is localization, not a transfer of every reaction’s permeability or subtype composition to all alpha4 receptors.

Summary: Retain the explicitly represented plasma-membrane location.

Reason: Official Reactome:R-HSA-622326 was followed through its receptor/catalyst entities to human P43681 entity 507836, with plasma-membrane compartment. The calcium-permeable set explicitly contains alpha4 assemblies. This source assertion is localization, not a transfer of every reaction’s permeability or subtype composition to all alpha4 receptors.

Summary: Retain the explicitly represented plasma-membrane location.

Reason: Official Reactome:R-HSA-629588 was followed through its receptor/catalyst entities to human P43681 entity 507836, with plasma-membrane compartment. The highly sodium-permeable set explicitly contains the alpha4(2)-beta2(3) assembly. This source assertion is localization, not a transfer of every reaction’s permeability or subtype composition to all alpha4 receptors.

Summary: Retain the explicitly represented plasma-membrane location.

Reason: Official Reactome:R-HSA-629595 was followed through its receptor/catalyst entities to human P43681 entity 507836, with plasma-membrane compartment. The modeled postsynaptic receptor set includes alpha4 among alternative receptor subunits; this is set membership, not proof that each possible combination is physiological. This source assertion is localization, not a transfer of every reaction’s permeability or subtype composition to all alpha4 receptors.

Summary: Retain the explicitly represented plasma-membrane location.

Reason: Official Reactome:R-HSA-629596 was followed through its receptor/catalyst entities to human P43681 entity 507836, with plasma-membrane compartment. The modeled postsynaptic receptor set includes alpha4 among alternative receptor subunits; this is set membership, not proof that each possible combination is physiological. This source assertion is localization, not a transfer of every reaction’s permeability or subtype composition to all alpha4 receptors.

Summary: Retain the explicitly represented plasma-membrane location.

Reason: Official Reactome:R-HSA-629599 was followed through its receptor/catalyst entities to human P43681 entity 507836, with plasma-membrane compartment. The calcium-permeable set explicitly contains alpha4 assemblies. This source assertion is localization, not a transfer of every reaction’s permeability or subtype composition to all alpha4 receptors.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: Original PMID:17132685 abstract explicitly compares alpha4beta2 stoichiometries and concatamers; full Methods remain unavailable. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: PMID:20881005 directly uses human beta2-alpha4-beta2-alpha4 concatamers with alpha5 in Xenopus oocytes; the alpha5 risk variant is not an alpha4 mutation. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: PMID:27698419 resolves a human 2alpha:3beta structure with intracellular-loop deletions and independently tests full-length receptor currents. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: PMID:29720657 resolves both 2alpha:3beta and 3alpha:2beta human receptor assemblies; the structural construct and Fab-assisted preparation are scoped separately from native brain receptors. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: PMID:38454578 combines human receptor cryo-EM and single-channel recordings; full-length structural chains contain Bril inserts and are distinguished from intracellular-loop-truncated preparations. No native untagged structure or identical behavior of both current products is assumed. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: The authentic PMID:8906617 abstract explicitly expresses human alpha4 with beta2 or beta4 in Xenopus oocytes and reports agonist-evoked currents; full original body remains unavailable. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Retain membership in the acetylcholine receptor complex.

Reason: The original domain/orthology inference is independently corroborated by human receptor assemblies. Alpha4 is a heteropentamer subunit; these studies do not establish identical behavior of both current splice products.

Summary: Leave the source-specific stress/repair assertion unresolved.

Reason: The authentic PMID:16332175 abstract associates human CHRNA4 polymorphisms with oxidative DNA lesions and apoptotic/repair-protein levels in Alzheimer-disease lymphocytes. Bounded publisher/indexed recovery did not obtain the full original Methods/Results. The abstract does not establish a CHRNA4-performed repair step, but cannot exclude evidence seen by the experimental curator. Preserve the original IMP/source without claiming direct repair activity or removing it from abstract-only evidence.

Summary: Specify the transmembrane movement of cations.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Human receptor currents identify a cation-conducting membrane pore, supporting GO:0098655 as the informative refinement of broad ion transport. This converges with existing channel evidence and creates no NEW process. The exact original domain, orthology or literature assertion remains preserved.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Specify the transmembrane movement of cations.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Human receptor currents identify a cation-conducting membrane pore, supporting GO:0098655 as the informative refinement of broad ion transport. This converges with existing channel evidence and creates no NEW process. The exact original domain, orthology or literature assertion remains preserved.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Retain calcium conduction by alpha4-containing receptors.

Reason: PMID:20881005 measures calcium-only currents through reconstituted human alpha4beta2alpha5 receptors using chloride-free solutions. Calcium permeability varies with stoichiometry and accessory subunits; it is not uniformly high or an isolated-alpha4 property.

Summary: Retain calcium conduction by alpha4-containing receptors.

Reason: PMID:20881005 measures calcium-only currents through reconstituted human alpha4beta2alpha5 receptors using chloride-free solutions. Calcium permeability varies with stoichiometry and accessory subunits; it is not uniformly high or an isolated-alpha4 property. The mouse O70174 ISS source is retained and independently corroborated by human receptor measurements.

Summary: Leave the source-specific stress/repair assertion unresolved.

Reason: The authentic PMID:16332175 abstract associates human CHRNA4 polymorphisms with oxidative DNA lesions and apoptotic/repair-protein levels in Alzheimer-disease lymphocytes. Bounded publisher/indexed recovery did not obtain the full original Methods/Results. The abstract does not establish a CHRNA4-performed repair step, but cannot exclude evidence seen by the experimental curator. Preserve the original IMP/source without claiming direct repair activity or removing it from abstract-only evidence.

Summary: Specify acetylcholine receptor signaling.

Reason: PMID:8906617 explicitly reports agonist-evoked currents in receptors assembled with human alpha4. GO:0095500 captures the ligand-triggered signaling event more precisely than generic signal transduction; independent full human receptor experiments corroborate the same performed step.

Proposed replacements: acetylcholine receptor signaling pathway

Summary: Specify cholinergic synaptic transmission.

Reason: The original PMID:7550350 human-family study links an alpha4 pore-domain variant to nocturnal epilepsy and describes its cortical expression. Independent human receptor function establishes the acetylcholine-responsive transmission step. Refine the existing broad transmission assertion to cholinergic transmission; do not attribute a modern patch-clamp assay to the original case report.

Proposed replacements: synaptic transmission, cholinergic

Summary: Retain cholinergic transmission mediated by alpha4 receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The existing source is retained at the receptor’s performed ligand-to-current step, not used to infer a specific neuronal circuit solely from heterologous expression.

Summary: Retain cholinergic transmission mediated by alpha4 receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The existing source is retained at the receptor’s performed ligand-to-current step, not used to infer a specific neuronal circuit solely from heterologous expression. The exact source construct/stoichiometry and ortholog limits are recorded with its reference.

Summary: Retain cholinergic transmission mediated by alpha4 receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The existing source is retained at the receptor’s performed ligand-to-current step, not used to infer a specific neuronal circuit solely from heterologous expression. The exact source construct/stoichiometry and ortholog limits are recorded with its reference.

Summary: Retain cholinergic transmission mediated by alpha4 receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The existing source is retained at the receptor’s performed ligand-to-current step, not used to infer a specific neuronal circuit solely from heterologous expression. The exact source construct/stoichiometry and ortholog limits are recorded with its reference.

Summary: Retain cholinergic transmission mediated by alpha4 receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The existing source is retained at the receptor’s performed ligand-to-current step, not used to infer a specific neuronal circuit solely from heterologous expression. The exact source construct/stoichiometry and ortholog limits are recorded with its reference.

Summary: Retain cholinergic transmission mediated by alpha4 receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The existing source is retained at the receptor’s performed ligand-to-current step, not used to infer a specific neuronal circuit solely from heterologous expression. The exact source construct/stoichiometry and ortholog limits are recorded with its reference.

Summary: Leave the neuromuscular transmission propagation unresolved.

Reason: The official term concerns transmission from a neuron to muscle. Alpha4 has strong neuronal receptor evidence, while the preserved PTN000436077 assertion includes human/zebrafish alpha1 and human/mouse alpha3 descendants. Current official records identify MGI:87887 as mouse Chrna3, not alpha1; they do not reconstruct the ancestral node. Historical IBD placement and target-specific neuromuscular evidence have not been independently resolved. This is not rejected from donor count or neuronal predominance; retain the exact ancestral assertion pending that specific scope check.

Summary: Retain the extracellular face of the surface receptor.

Reason: Alpha4’s ligand-recognition domain faces the extracellular space in human receptor structures. The original mouse O70174 transfer is also supported by its current surface-assay record PMID:15963492; the latter’s authentic abstract describes cell ELISA/ligand binding in mouse B cells, not a human neuronal localization experiment.

Summary: Retain the extracellular face of the surface receptor.

Reason: Alpha4’s ligand-recognition domain faces the extracellular space in human receptor structures. The original mouse O70174 transfer is also supported by its current surface-assay record PMID:15963492; the latter’s authentic abstract describes cell ELISA/ligand binding in mouse B cells, not a human neuronal localization experiment.

Summary: Retain presynaptic control of dopamine release.

Reason: Actual PMID:12944511 compares wild-type and alpha4-null mouse striatal synaptosomes and shows reduced nicotine-evoked dopamine release; receptor antagonists and calcium dependence resolve the nicotinic mechanism. Alpha4-containing presynaptic channels perform a modulatory step. This supports the existing mouse-derived human ISS at a circuit-specific, non-core scope; it does not establish dopamine synthesis or transport by alpha4.

Summary: Specify the acetylcholine-gated cation-channel activity.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The official broad receptor/channel terms can be refined to GO:0022848; GO:0015464 explicitly directs nicotinic ion channels to that term. The original PMID:20438829 abstract concerns ethanol exposure and CHRNA5 expression; its full alpha4-specific context is unverified. This refinement rests on independently inspected human receptor experiments, not a wrong-paralog allegation. The action adjudicates target function from those independent experiments; it does not verify the original TAS citation linkage.

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

Summary: Specify the acetylcholine-gated cation-channel activity.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The official broad receptor/channel terms can be refined to GO:0022848; GO:0015464 explicitly directs nicotinic ion channels to that term. Original evidence, qualifier and family/orthology sources remain unchanged.

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

Summary: Specify the acetylcholine-gated cation-channel activity.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The official broad receptor/channel terms can be refined to GO:0022848; GO:0015464 explicitly directs nicotinic ion channels to that term. Original evidence, qualifier and family/orthology sources remain unchanged.

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

Summary: Specify the plasma membrane for functional receptor molecules.

Reason: The original broad membrane assertion is valid, and independently measured human surface receptor currents justify the more informative plasma-membrane compartment. This does not claim every nascent or unassembled splice product is restricted to the cell surface.

Proposed replacements: plasma membrane

Summary: Specify the plasma membrane for functional receptor molecules.

Reason: The original broad membrane assertion is valid, and independently measured human surface receptor currents justify the more informative plasma-membrane compartment. This does not claim every nascent or unassembled splice product is restricted to the cell surface.

Proposed replacements: plasma membrane

Summary: Specify the plasma membrane for functional receptor molecules.

Reason: The original broad membrane assertion is valid, and independently measured human surface receptor currents justify the more informative plasma-membrane compartment. This does not claim every nascent or unassembled splice product is restricted to the cell surface.

Proposed replacements: plasma membrane

Summary: Retain the ortholog-supported pain-response context.

Reason: The original mouse O70174 record points to PMID:10235262. Its authentic abstract reports alpha4-null mice with diminished nicotine antinociception in hot-plate and tail-flick tests. Preserve this contextual phenotype and its ISS scope, without turning it into a separate pain-sensing molecular activity or claiming inspection of the unavailable full original Methods.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Preserve the original evidence and qualifier; structural preparations and direct functional assays are distinguished in the source assessment.

Summary: Retain the defining acetylcholine-gated cation-channel function.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The original PMID:20438829 full target-specific context remains inaccessible; independent human functional sources establish the retained activity without alleging miscitation from its CHRNA5-focused abstract. The action adjudicates target function from those independent experiments; it does not verify the original TAS citation linkage.

Summary: Retain the ortholog-supported dendritic pool.

Reason: The exact rat P09483 orthology source and current corresponding donor annotations are retained. Rodent alpha4-containing receptors occur in somatodendritic and presynaptic compartments; this is compartmental specialization of the receptor, not a human all-cell or all-product localization claim. The historical donor transfer was not reconstructed.

Summary: Specify the transmembrane movement of cations.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Human receptor currents identify a cation-conducting membrane pore, supporting GO:0098655 as the informative refinement of broad ion transport. This converges with existing channel evidence and creates no NEW process.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Specify the transmembrane movement of cations.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Human receptor currents identify a cation-conducting membrane pore, supporting GO:0098655 as the informative refinement of broad ion transport. This converges with existing channel evidence and creates no NEW process. The exact original domain, orthology or literature assertion remains preserved.

Proposed replacements: monoatomic cation transmembrane transport

Summary: Retain the pharmacological response to nicotine.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. Nicotine is an experimentally established agonist of alpha4-containing receptors, while acetylcholine is the defining endogenous ligand.

Summary: Retain the measured endothelial response to nicotine.

Reason: Actual PMID:12189247 reports alpha4 and beta2 expression following the alpha7 nicotine-response pattern, as data not shown. Retain this source-specific expression response separately from the paper’s alpha7-dependent angiogenesis experiments; no alpha4-specific angiogenic core is inferred.

Summary: Leave the prenatal-exposure behavioral assertion unresolved.

Reason: PMID:17955458’s authentic abstract reports a human CHRNA4 genotype-by-maternal-smoking association with childhood ADHD risk. Full original methods/results were not recovered after bounded publisher attempts. Prenatal exposure association is not automatically a measured nicotine-evoked behavior of the carrier, but abstract-only access does not justify removing the original IMP.

Summary: The specific human behavioral claim remains unresolved across its sources.

Reason: Actual full PMID:20881005 tests human receptor currents, calcium permeability and desensitization in Xenopus oocytes and tsA201 cells. Alpha5 Asp398/Asn398 modifies alpha4-containing receptor responses; no behavioral experiment is performed in that study. Its discussion cites independent alpha4 mouse self-administration work, which is not denied. GO:0035094 captures the measured pharmacological response at this source’s scope. The same-term association row remains unresolved, so the judgment of the biological claim is consistently UNDECIDED across both rows. The direct cellular nicotine response is independently represented; the source mismatch does not establish that the human behavioral role is false.

Summary: Retain the mouse-supported B-cell activation context.

Reason: The exact mouse donor has experimental PMID:15963492 annotations; its authentic abstract reports altered B-cell CD40 responsiveness and IgG after alpha4 loss, together with nicotinic receptor surface assays. This supports the existing ISS as a non-neuronal context, without claiming alpha4 executes antibody synthesis or that the full original assay details were inspected.

Summary: Retain alpha4’s contribution to acetylcholine recognition.

Reason: The original IC follows functional acetylcholine activation of human alpha4-containing receptors in PMID:8906617. Independent full human receptor work establishes ligand interfaces and currents. This binding contribution belongs to the assembled receptor and is not a claim of isolated-alpha4 autonomous ligand binding.

Summary: Retain regulation of neuronal membrane potential.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The receptor’s inward current depolarizes the membrane; the preserved mouse-derived source is independently corroborated by human receptor physiology. No voltage-gated alpha4 activity is inferred.

Summary: Retain the presynaptic receptor pool.

Reason: Mouse PMID:12944511 establishes alpha4-containing receptors in dopamine terminal fields and nicotine-stimulated release. Rat PMID:22593584 uses N-terminally tagged rat alpha4 with beta2/neurexin-1beta and shows conditional targeting to presynaptic contacts in neuronal coculture. The original rodent orthology is preserved; engineered targeting is not equated with universal native localization.

Summary: Retain the presynaptic receptor pool.

Reason: Mouse PMID:12944511 establishes alpha4-containing receptors in dopamine terminal fields and nicotine-stimulated release. Rat PMID:22593584 uses N-terminally tagged rat alpha4 with beta2/neurexin-1beta and shows conditional targeting to presynaptic contacts in neuronal coculture. The original rodent orthology is preserved; engineered targeting is not equated with universal native localization.

Summary: Retain the presynaptic receptor pool.

Reason: Mouse PMID:12944511 establishes alpha4-containing receptors in dopamine terminal fields and nicotine-stimulated release. Rat PMID:22593584 uses N-terminally tagged rat alpha4 with beta2/neurexin-1beta and shows conditional targeting to presynaptic contacts in neuronal coculture. Original PMID:20881005 discusses presynaptic alpha4beta2alpha5 receptors but does not itself image endogenous human presynapses.

Summary: Retain the ortholog-supported neuronal cell-body pool.

Reason: The exact rat P09483 orthology source and current corresponding donor annotations are retained. Rodent alpha4-containing receptors occur in somatodendritic and presynaptic compartments; this is compartmental specialization of the receptor, not a human all-cell or all-product localization claim. The historical donor transfer was not reconstructed.

Summary: Retain the synaptic membrane receptor location.

Reason: Alpha4-containing receptors mediate postsynaptic cholinergic conductance and can also modulate transmitter release presynaptically. The original synaptic-compartment inference is retained at that receptor pool, without claiming exclusive postsynaptic expression or transferring an exact rodent cell type to every human neuron.

Summary: Retain the synaptic membrane receptor location.

Reason: Alpha4-containing receptors mediate postsynaptic cholinergic conductance and can also modulate transmitter release presynaptically. The original synaptic-compartment inference is retained at that receptor pool, without claiming exclusive postsynaptic expression or transferring an exact rodent cell type to every human neuron. Original donor/domain fields remain unchanged.

Summary: Retain the broad human nervous-system context.

Reason: Recovered full PMID:17613539 studies 47 healthy participants using synonymous CHRNA4 variants and visual-oddball fMRI. Genotype-associated network responses occur without a demonstrated causal molecular variant mechanism or a corresponding overt task-performance effect. This supports the broad existing nervous-system assertion non-core, not a new attention-specific molecular activity.

Summary: Retain the human neuronal disease context.

Reason: The authentic PMID:7550350 abstract reports a segregating pore-domain CHRNA4 variant in a large nocturnal-epilepsy family. Together with independent human channel measurements this supports the broad existing nervous-system role. Full original body was not recovered; no specific electrophysiological protocol is attributed to that report.

Summary: Retain cognition as a contextual human phenotype.

Reason: The authentic PMID:14623738 abstract describes neuropsychological evaluation of a Korean CHRNA4 Ser252Leu kindred and cognitive impairment among tested affected members. Preserve the broad existing cognition assertion at this disease-phenotype scope; the source does not isolate cognition from seizures or define a separate cognitive molecular mechanism. Full body was not recovered.

Summary: Retain the depolarizing effect of alpha4-containing receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. This supports membrane depolarization and excitatory postsynaptic current in the receptor-bearing cell, while downstream circuit effects may be inhibitory.

Summary: Retain the depolarizing effect of alpha4-containing receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. This supports membrane depolarization and excitatory postsynaptic current in the receptor-bearing cell, while downstream circuit effects may be inhibitory. The original orthology or logical channel-to-process inference remains unchanged.

Summary: Retain the depolarizing effect of alpha4-containing receptors.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. This supports membrane depolarization and excitatory postsynaptic current in the receptor-bearing cell, while downstream circuit effects may be inhibitory. The original orthology or logical channel-to-process inference remains unchanged.

Summary: Specify modulation of inhibitory postsynaptic potential.

Reason: Actual full PMID:17146052 tests mouse alpha4 S252F and +L264 variants and finds enhanced nicotine-evoked GABAergic IPSCs in cortical pyramidal cells. Pharmacology and miniature-current experiments implicate receptors on interneurons/terminals; the receiving cell’s GABA receptor carries the inhibitory current. GO:0098828 captures alpha4-dependent modulation without implying an anion-conducting alpha4 pore. Retain the original mouse-derived ISS/source fields.

Proposed replacements: modulation of inhibitory postsynaptic potential

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step.

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step. No additional downstream transcriptional or developmental mechanism is inferred from the heterologous receptor assays.

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step. No additional downstream transcriptional or developmental mechanism is inferred from the heterologous receptor assays.

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step. No additional downstream transcriptional or developmental mechanism is inferred from the heterologous receptor assays.

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step. No additional downstream transcriptional or developmental mechanism is inferred from the heterologous receptor assays.

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step. No additional downstream transcriptional or developmental mechanism is inferred from the heterologous receptor assays.

Summary: Retain ligand-triggered acetylcholine receptor signaling.

Reason: Human alpha4-containing heteropentamers have directly measured acetylcholine-evoked currents. Alpha4 contributes ligand interfaces and the shared pore; it is not an autonomous homomeric channel. The measured ligand-to-current conversion is the performed signaling step. No additional downstream transcriptional or developmental mechanism is inferred from the heterologous receptor assays.

Summary: Retain the synaptic membrane receptor location.

Reason: Alpha4-containing receptors mediate postsynaptic cholinergic conductance and can also modulate transmitter release presynaptically. The original synaptic-compartment inference is retained at that receptor pool, without claiming exclusive postsynaptic expression or transferring an exact rodent cell type to every human neuron. Original donor/domain fields remain unchanged.

Summary: Retain the synaptic membrane receptor location.

Reason: Alpha4-containing receptors mediate postsynaptic cholinergic conductance and can also modulate transmitter release presynaptically. The original synaptic-compartment inference is retained at that receptor pool, without claiming exclusive postsynaptic expression or transferring an exact rodent cell type to every human neuron. Original donor/domain fields remain unchanged.

Summary: Retain the dopaminergic-synapse specialization.

Reason: The exact mouse donor is preserved. Actual PMID:12944511 localizes alpha4-containing receptors in striatal dopamine terminal fields and demonstrates their contribution to nicotine-stimulated dopamine release. This supports the contextual synaptic specialization without implying dopamine synthesis or an exclusive dopaminergic distribution.

Summary: Retain the performed presynaptic modulatory role.

Reason: Actual PMID:12944511 uses mouse receptor composition, genetic loss and striatal synaptosomal release measurements to resolve alpha4-dependent modulation of transmitter release. This is receptor-driven presynaptic work, not merely a downstream behavioral phenotype.

Summary: Retain the performed presynaptic modulatory role.

Reason: Actual PMID:12944511 uses mouse receptor composition, genetic loss and striatal synaptosomal release measurements to resolve alpha4-dependent modulation of transmitter release. This is receptor-driven presynaptic work, not merely a downstream behavioral phenotype. The exact current mouse/Ensembl source remains distinct from independently read rodent primary corroboration.