CHRM3 encodes the M3 muscarinic acetylcholine receptor, a seven-transmembrane receptor that predominantly activates Gq/11, phospholipase C and calcium signaling. It regulates smooth-muscle contraction and exocrine secretion, including intestinal and salivary responses. The receptor can occupy basolateral epithelial membranes, and TMEM147 can retain a pool in the endoplasmic reticulum. Its signaling repertoire is context dependent: human M3 associates with NALCN in heterologous cells, while a Src-dependent, G-protein-independent channel response was studied in a mouse pancreatic beta-cell line.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004435 phosphatidylinositol-4,5-bisphosphate phospholipase C activity | IEA GO_REF:0000117 | REMOVE | Summary: M3 activates a PLC pathway but is not the PIP2-hydrolyzing enzyme. Reason: The live GO definition requires catalysis of phosphatidylinositol-4,5-bisphosphate hydrolysis. The muscarinic product is a seven-transmembrane receptor; receptor-driven G-protein activation stimulates a separate PLC enzyme. The original pharmacological readout measures downstream phosphoinositide hydrolysis, not catalytic conversion by the receptor. The receptor activity and PLC-coupled process are retained. Supporting Evidence: PMID:31073061 By contrast, M1R, M3R, and M5R predominantly couple to Gq/11 proteins (Gq and G11), leading to the activation of phospholipase C and the increase of cytosolic Ca2+ |
| GO:0004435 phosphatidylinositol-4,5-bisphosphate phospholipase C activity | TAS PMID:1905013 Muscarinic acetylcholine receptor subtypes as agonist-depend... | REMOVE | Summary: M3 activates a PLC pathway but is not the PIP2-hydrolyzing enzyme. Reason: The live GO definition requires catalysis of phosphatidylinositol-4,5-bisphosphate hydrolysis. The muscarinic product is a seven-transmembrane receptor; receptor-driven G-protein activation stimulates a separate PLC enzyme. The original pharmacological readout measures downstream phosphoinositide hydrolysis, not catalytic conversion by the receptor. The receptor activity and PLC-coupled process are retained. Supporting Evidence: PMID:31073061 By contrast, M1R, M3R, and M5R predominantly couple to Gq/11 proteins (Gq and G11), leading to the activation of phospholipase C and the increase of cytosolic Ca2+ |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: M3 is specifically a G-protein-coupled acetylcholine receptor. Reason: The human cloned receptor binds muscarinic ligands and activates G-protein signaling. Refine the broad receptor activity to the already-supported acetylcholine receptor activity; this does not transfer an effector enzyme activity to the receptor. Proposed replacements: G protein-coupled acetylcholine receptor activity |
| GO:0005515 protein binding | IPI PMID:19575010 The NALCN ion channel is activated by M3 muscarinic receptor... | MODIFY | Summary: M3 associates with the NALCN transmembrane channel complex. Reason: Full primary Methods identify human M3 and human NALCN constructs in HEK293 cells; co-IP and intracellular-fragment experiments support the specific transporter-partner class. The authors leave direct contact versus co-inclusion in a larger complex unresolved. Refine to transmembrane transporter binding, retaining that assay limitation; a direct channel-regulator activity requiring direct contact is not inferred. Proposed replacements: transmembrane transporter binding Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2710536/ It remains to be determined whether this is through a direct interaction or through co-inclusion in a larger protein complex. |
| GO:0005515 protein binding | IPI PMID:20398705 The M(5) muscarinic acetylcholine receptor third intracellul... | MODIFY | Summary: M3 physically associates with the M5 GPCR in heterologous cells. Reason: Coimmunoprecipitation and BRET support M3-M5 heteromeric association in transfected HEK293T cells, allowing the specific GPCR-binding refinement. This does not establish an obligatory native heterodimer or assign M5 signaling outputs to M3. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:20398705 M(3) and M(5) muscarinic receptors could form constitutive homo- and heterodimers in transiently transfected HEK-293T cells. |
| GO:0005515 protein binding | IPI PMID:21056967 Regulation of Mβ muscarinic receptor expression and function... | REMOVE | Summary: The reported M3 interaction is preserved without a bare binding function. Reason: The original PMID:21056967 records association with UniProtKB:Q9BVK8. The generic protein-binding term adds no mechanistic information about ligand recognition, G-protein activation or trafficking. Remove this uninformative annotation under the binding policy without rejecting the measured association or inferring a new function from the partner name. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: The reported M3 interaction is preserved without a bare binding function. Reason: The original PMID:39083597 records association with UniProtKB:O60895. The generic protein-binding term adds no mechanistic information about ligand recognition, G-protein activation or trafficking. Remove this uninformative annotation under the binding policy without rejecting the measured association or inferring a new function from the partner name. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: The reported M3 interaction is preserved without a bare binding function. Reason: The original PMID:39083597 records association with UniProtKB:O60896. The generic protein-binding term adds no mechanistic information about ligand recognition, G-protein activation or trafficking. Remove this uninformative annotation under the binding policy without rejecting the measured association or inferring a new function from the partner name. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:21056967 Regulation of Mβ muscarinic receptor expression and function... | ACCEPT | Summary: M3 has a demonstrated endoplasmic-reticulum membrane pool. Reason: TMEM147-associated retention was visualized in cotransfected COS-7 cells, and endogenous H508 perturbations support regulation of M3 surface availability. Retain the actual ER pool while distinguishing heterologous localization from a universal native ER-signaling mechanism. Supporting Evidence: PMID:21056967 the Tmem147/M3R interaction occurred in the ER of cotransfected COS-7 cells file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: M3 has a demonstrated endoplasmic-reticulum membrane pool. Reason: TMEM147-associated retention was visualized in cotransfected COS-7 cells, and endogenous H508 perturbations support regulation of M3 surface availability. Retain the actual ER pool while distinguishing heterologous localization from a universal native ER-signaling mechanism. Supporting Evidence: PMID:21056967 the Tmem147/M3R interaction occurred in the ER of cotransfected COS-7 cells file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. Original ancestral source: PANTHER:PTN000664111. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | IDA PMID:21056967 Regulation of Mβ muscarinic receptor expression and function... | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS PMID:3443095 Distinct primary structures, ligand-binding properties and t... | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS PMID:9547368 The relationship between agonist intrinsic activity and the ... | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-390649 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9704151 | ACCEPT | Summary: M3 signals from a plasma-membrane receptor pool. Reason: Human receptor expression and ligand/signaling experiments support surface localization, together with curated subcellular information. The original Reactome signaling or internalization intermediates are compatible with this pool. Surface localization is not used to exclude separately supported internal membranes. |
| GO:0006940 regulation of smooth muscle contraction | IBA GO_REF:0000033 | MODIFY | Summary: M3 promotes smooth-muscle contraction through muscarinic signaling. Reason: The conserved regulatory process can be refined to the positive regulation already assigned to M3, consistent with its calcium-linked contractile role. Tissue-specific coupling and other muscarinic subtypes do not invalidate this supported direction. Original ancestral source: PANTHER:PTN002797896. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002797896 UNRESOLVED The inherited broad function is retained as biologically sound and refined using independent target evidence. No failure of ancestral-node placement or donor count is alleged; the complete historical node reconstruction was not inspected. Proposed replacements: positive regulation of smooth muscle contraction |
| GO:0007165 signal transduction | TAS PMID:10940357 Effect of dimethylsphingosine on muscarinic M(3) receptor si... | MODIFY | Summary: M3 transduces acetylcholine signals through a muscarinic GPCR pathway. Reason: The broad signaling assertion is sound, and the receptor-specific G-protein-coupled acetylcholine pathway is already established. This process term accommodates context-dependent downstream outputs rather than equating all receptor signaling with a single measured effector. Proposed replacements: G protein-coupled acetylcholine receptor signaling pathway Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | MODIFY | Summary: M3 transduces acetylcholine signals through a muscarinic GPCR pathway. Reason: The broad signaling assertion is sound, and the receptor-specific G-protein-coupled acetylcholine pathway is already established. This process term accommodates context-dependent downstream outputs rather than equating all receptor signaling with a single measured effector. Proposed replacements: G protein-coupled acetylcholine receptor signaling pathway Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:9603968 Muscarinic acetylcholine receptors activate expression of th... | MODIFY | Summary: M3 transduces acetylcholine signals through a muscarinic GPCR pathway. Reason: The broad signaling assertion is sound, and the receptor-specific G-protein-coupled acetylcholine pathway is already established. This process term accommodates context-dependent downstream outputs rather than equating all receptor signaling with a single measured effector. Proposed replacements: G protein-coupled acetylcholine receptor signaling pathway Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0007187 G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: M3 can engage cyclic-nucleotide responses in particular cells. Reason: Human receptor-expression comparisons show cAMP stimulation in CHO-M3 cells, with lower efficiency than M1 and sensitivity to expression level. The broader cyclic-nucleotide process is warranted without imposing an inhibitory sign on all M3 responses. Original ancestral source: PANTHER:PTN000664111. |
| GO:0007197 adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway | IBA GO_REF:0000033 | UNDECIDED | Summary: The exact M3 cyclase-inhibitory branch is not established by the inspected assays. Reason: The PAINT source includes the M2/M4 inhibitory receptor branch, while direct human M3 experiments establish Gi activation and context-dependent cAMP increases. Gi activation alone does not demonstrate inhibition of a particular cyclase. These observations neither refute all possible M3 inhibitory contexts nor establish the complete process asserted here; further target-specific effector evidence is needed. Original ancestral source: PANTHER:PTN001207082. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001207082 UNRESOLVED The PAINT source includes the M2/M4 inhibitory receptor branch, while direct human M3 experiments establish Gi activation and context-dependent cAMP increases. Gi activation alone does not demonstrate inhibition of a particular cyclase. These observations neither refute all possible M3 inhibitory contexts nor establish the complete process asserted here; further target-specific effector evidence is needed. Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0007207 phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: M3 directly initiates the PLC-activating muscarinic pathway. Reason: Human M3 activates Gq/11 in receptor-specific assays, and phosphoinositide/calcium responses independently establish this downstream pathway. The receptor performs activation while PLC performs phospholipid hydrolysis. Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0007213 G protein-coupled acetylcholine receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: M3 initiates G-protein-coupled acetylcholine signaling. Reason: The receptor itself performs ligand recognition and G-protein activation, so pathway participation is direct. This informative pathway-level term is retained alongside specific downstream signaling branches; it does not assert that all branches occur simultaneously in every tissue. Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0007268 chemical synaptic transmission | IBA GO_REF:0000033 | ACCEPT | Summary: M3 performs the receptor step of chemical synaptic signaling. Reason: Recognition of released acetylcholine and receptor-mediated signaling are direct functions in neurotransmission. The inherited neuronal process is not restricted to fast nicotinic ion-channel transmission; muscarinic modulation is a genuine synaptic contribution. Original ancestral source: PANTHER:PTN000664111. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0007399 nervous system development | TAS PMID:2739737 Acetylcholine analogue stimulates DNA synthesis in brain-der... | KEEP AS NON CORE | Summary: M3-linked mitogenic signaling can contribute to nervous-system cellular growth. Reason: The original study links muscarinic PI signaling to proliferation in primary rat astrocytes and brain-derived cells, with receptor-expressing CHO comparisons. Retain the developmental context with its cell-system limits; do not turn this into a universal human developmental requirement or assign DNA-synthesis catalysis to M3. Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0009925 basal plasma membrane | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | UNDECIDED | Summary: Basal versus broader basolateral M3 localization is not resolved from the accessible source. Reason: The native human colonic study explicitly examines M3 immunolocalization and cholinergic calcium responses, so it is relevant. The recovered abstract does not resolve the basal-only membrane detail and full figures remained inaccessible through the attempted PMC routes. Independent basolateral localization supports a nearby but not identical spatial assertion; no absence of a basal pool is claimed. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The M3 membrane assignment can be refined to supported membrane compartments. Reason: The broad membrane term is correct; publication-linked or curated localization identifies plasma membrane, endoplasmic-reticulum membrane and basolateral epithelial membrane pools. |
| GO:0016323 basolateral plasma membrane | EXP PMID:15870063 Identification and structural determination of the M(3) musc... | ACCEPT | Summary: M3 can be targeted to the basolateral epithelial membrane. Reason: The original receptor-sorting study defines a basolateral targeting signal and the publication-linked curated record retains this location. This is a specific epithelial context, not a general neuronal polarity assertion. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt Basolateral cell membrane CC {ECO:0000269|PubMed:15870063} |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: M3 can be targeted to the basolateral epithelial membrane. Reason: The original receptor-sorting study defines a basolateral targeting signal and the publication-linked curated record retains this location. This is a specific epithelial context, not a general neuronal polarity assertion. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt Basolateral cell membrane CC {ECO:0000269|PubMed:15870063} |
| GO:0016907 G protein-coupled acetylcholine receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Human M3 has directly established muscarinic acetylcholine-receptor activity. Reason: Human receptor cloning, pharmacology and functional signaling independently support the specific ligand-receptor class. The conserved family assignment agrees with the target evidence; agonist efficacy and coupling preferences remain dependent on the experimental system. Original ancestral source: PANTHER:PTN001207082. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0016907 G protein-coupled acetylcholine receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Human M3 has directly established muscarinic acetylcholine-receptor activity. Reason: Human receptor cloning, pharmacology and functional signaling independently support the specific ligand-receptor class. The conserved family assignment agrees with the target evidence; agonist efficacy and coupling preferences remain dependent on the experimental system. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0016907 G protein-coupled acetylcholine receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Human M3 has directly established muscarinic acetylcholine-receptor activity. Reason: Human receptor cloning, pharmacology and functional signaling independently support the specific ligand-receptor class. The conserved family assignment agrees with the target evidence; agonist efficacy and coupling preferences remain dependent on the experimental system. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0016907 G protein-coupled acetylcholine receptor activity | TAS PMID:9547368 The relationship between agonist intrinsic activity and the ... | ACCEPT | Summary: Human M3 has directly established muscarinic acetylcholine-receptor activity. Reason: Human receptor cloning, pharmacology and functional signaling independently support the specific ligand-receptor class. The conserved family assignment agrees with the target evidence; agonist efficacy and coupling preferences remain dependent on the experimental system. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0019722 calcium-mediated signaling | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | ACCEPT | Summary: M3 drives calcium-mediated signaling. Reason: The original native human colonic study measures cholinergic calcium responses and receptor localization. Independent human receptor/Gq assays support the mechanism; neither calcium binding nor a calcium-channel pore is assigned to M3 itself. Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0030425 dendrite | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited dendritic localization is compatible with M3 neuronal receptor function. Reason: The PAINT neuronal-compartment placement and curated mammalian muscarinic receptor localization support a dendritic pool. No target-specific evidence of loss or redistribution excludes this inference. It is retained as a conserved localization judgment, not misrepresented as imaging of native human dendrites in a heterologous signaling assay. Original ancestral source: PANTHER:PTN000664111. Subtype-specific rat striatal microscopy (PMID:8182478) independently identifies the corresponding neuronal compartments; this is comparative evidence, not direct human imaging. |
| GO:0036211 protein modification process | TAS PMID:10051746 Distribution of histamine H3-receptor binding in the normal ... | UNDECIDED | Summary: The protein-modification claim has an unresolved reference-to-function link. Reason: PMID:10051746 describes human basal-ganglia histamine H3 receptor autoradiography in the accessible record. Its full text was not recovered to verify any separate M3 experiment. Moreover, receptor phosphorylation alone would make M3 a substrate, not the modifier. The broad process remains unresolved rather than being rejected solely from the paper title or assumed to follow from any kinase response. |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: M3 is specifically a G-protein-coupled acetylcholine receptor. Reason: The human cloned receptor binds muscarinic ligands and activates G-protein signaling. Refine the broad receptor activity to the already-supported acetylcholine receptor activity; this does not transfer an effector enzyme activity to the receptor. Proposed replacements: G protein-coupled acetylcholine receptor activity |
| GO:0038023 signaling receptor activity | TAS PMID:10940357 Effect of dimethylsphingosine on muscarinic M(3) receptor si... | MODIFY | Summary: M3 is specifically a G-protein-coupled acetylcholine receptor. Reason: The human cloned receptor binds muscarinic ligands and activates G-protein signaling. Refine the broad receptor activity to the already-supported acetylcholine receptor activity; this does not transfer an effector enzyme activity to the receptor. Proposed replacements: G protein-coupled acetylcholine receptor activity |
| GO:0042166 acetylcholine binding | ISS GO_REF:0000024 | ACCEPT | Summary: Acetylcholine binding is integral to M3 receptor activation. Reason: The cloned human receptor pharmacology and ortholog-derived ligand-binding assignment agree on acetylcholine recognition. Integral ligand binding is a core biochemical property rather than a peripheral protein interaction. |
| GO:0045202 synapse | IBA GO_REF:0000033 | ACCEPT | Summary: M3 is a synaptically localized cholinergic receptor. Reason: The conserved synaptic localization is consistent with the receptor function and separately curated neuronal membrane pools. This compartment-level assertion remains informative without specifying only one synapse subtype. Original ancestral source: PANTHER:PTN001207082. Subtype-specific rat striatal microscopy (PMID:8182478) independently identifies the corresponding neuronal compartments; this is comparative evidence, not direct human imaging. |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000044 | ACCEPT | Summary: M3 has a supported postsynaptic membrane pool. Reason: The curated postsynaptic localization and conserved neuronal receptor role support this compartment. A presynaptic or nonsynaptic role in another context is not evidence against the postsynaptic pool. Subtype-specific rat striatal microscopy (PMID:8182478) independently identifies the corresponding neuronal compartments; this is comparative evidence, not direct human imaging. Supporting Evidence: file:human/CHRM3/CHRM3-uniprot.txt Postsynaptic cell membrane |
| GO:0045987 positive regulation of smooth muscle contraction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: M3 signaling promotes smooth-muscle contraction. Reason: Mammalian subtype physiology establishes the calcium-linked contractile role, with receptor signaling providing the regulatory step. Retain this tissue response without making it the only function of the receptor. Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins |
| GO:0046541 saliva secretion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: M3 is the principal low-threshold muscarinic driver of salivary secretion in the tested mouse system. Reason: Single and double receptor knockouts, acinar calcium imaging and dry-food behavior directly establish the secretory contribution. High agonist concentrations can recruit M1-dependent output, so the M3 role is strong but does not mean exclusive receptor control under all stimulation conditions. Human assignment is a conserved physiological inference. |
| GO:0095500 acetylcholine receptor signaling pathway | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | MODIFY | Summary: M3 transduces acetylcholine signals through a muscarinic GPCR pathway. Reason: The broad signaling assertion is sound, and the receptor-specific G-protein-coupled acetylcholine pathway is already established. This process term accommodates context-dependent downstream outputs rather than equating all receptor signaling with a single measured effector. Proposed replacements: G protein-coupled acetylcholine receptor signaling pathway Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins file:human/CHRM3/CHRM3-uniprot.txt |
| GO:0095500 acetylcholine receptor signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: M3 transduces acetylcholine signals through a muscarinic GPCR pathway. Reason: The broad signaling assertion is sound, and the receptor-specific G-protein-coupled acetylcholine pathway is already established. This process term accommodates context-dependent downstream outputs rather than equating all receptor signaling with a single measured effector. Proposed replacements: G protein-coupled acetylcholine receptor signaling pathway Supporting Evidence: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1572629/ activation of M1 and M3 mACh receptors resulted in enhanced [35S]-GTPΞ³S binding not only to Gq/11Ξ±, but also to Gi1/2Ξ± and Gi3/oΞ± proteins file:human/CHRM3/CHRM3-uniprot.txt |
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