RGS4 is a GTPase-activating regulator of heterotrimeric Gi/o and Gq signaling. Its RGS domain binds the activated G alpha subunit and stabilizes the transition state for GTP hydrolysis, shortening receptor-driven signaling. RGS4 acts at the cytoplasmic plasma-membrane surface and in the cytoplasm, with regulated nuclear shuttling. It modulates neurotransmitter-receptor control of calcium and potassium channels and can restrain cardiac hypertrophic signaling; receptor and cellular context determine its physiological effects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001965 G-protein alpha-subunit binding | IEA GO_REF:0000107 | ACCEPT | Summary: Purified RGS4 accelerates Gi-family GTP hydrolysis, and the RGS4–Gi1 transition-state structure directly identifies the G alpha-binding interface. Reason: These are integral molecular functions, not peripheral binding annotations. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0001975 response to amphetamine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat RGS4 expression in VTA and nucleus accumbens correlates with amphetamine intake in PMID:26321241. Reason: Retain the bounded stimulus-response inference without converting correlation into causal drug-seeking behavior. Supporting Evidence: |
| GO:0003924 GTPase activity | IEA GO_REF:0000117 | MODIFY | Summary: RGS4 stabilizes the transition state of G alpha-mediated GTP hydrolysis; it is a GAP, not itself the guanine-nucleotide-binding GTPase. Reason: Refine to its already represented GAP activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: ARBA:ARBA00026818 UNRESOLVED RGS4 stabilizes the transition state of G alpha-mediated GTP hydrolysis; it is a GAP, not itself the guanine-nucleotide-binding GTPase. Refine to its already represented GAP activity. Proposed replacements: GTPase activator activity Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0003924 GTPase activity | TAS Reactome:R-HSA-8982020 | MODIFY | Summary: RGS4 stabilizes the transition state of G alpha-mediated GTP hydrolysis; it is a GAP, not itself the guanine-nucleotide-binding GTPase. Reason: Refine to its already represented GAP activity. Proposed replacements: GTPase activator activity Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Purified RGS4 accelerates Gi-family GTP hydrolysis, and the RGS4–Gi1 transition-state structure directly identifies the G alpha-binding interface. Reason: These are integral molecular functions, not peripheral binding annotations. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000107 | ACCEPT | Summary: Purified RGS4 accelerates Gi-family GTP hydrolysis, and the RGS4–Gi1 transition-state structure directly identifies the G alpha-binding interface. Reason: These are integral molecular functions, not peripheral binding annotations. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005096 GTPase activator activity | TAS PMID:10747990 Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trispho... | ACCEPT | Summary: Purified RGS4 accelerates Gi-family GTP hydrolysis, and the RGS4–Gi1 transition-state structure directly identifies the G alpha-binding interface. Reason: These are integral molecular functions, not peripheral binding annotations. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005516 calmodulin binding | TAS PMID:10747990 Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trispho... | ACCEPT | Summary: PMID:10747990 explicitly demonstrates calcium-dependent calmodulin binding to RGS4, including a complex with activated Gi1, and reversal of PIP3-mediated GAP inhibition. Reason: Retain this regulatory ligand-binding function. Supporting Evidence: PMID:10747990 Ca(2+)/calmodulin binds a complex of RGS4 |
| GO:0005634 nucleus | IDA PMID:10791963 Cytoplasmic, nuclear, and golgi localization of RGS proteins... | KEEP AS NON CORE | Summary: Nuclear RGS4 is condition-dependent: PMID:10791963 reports nuclear accumulation after inhibition of export or alteration of its export determinants. Reason: Predominantly cytoplasmic steady-state localization does not negate that observed pool. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:10791963 Cytoplasmic, nuclear, and golgi localization of RGS proteins... | ACCEPT | Summary: RGS4 has a cytoplasmic signaling-regulator pool, directly supported by the localization experiments. Reason: Its regulated nuclear shuttling and membrane recruitment do not make cytoplasmic localization incorrect. Supporting Evidence: |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982012 | MODIFY | Summary: RGS4 acts on membrane-associated G alpha from the cytoplasmic face. Reason: Refine the broad plasma-membrane annotation to the separately retained cytoplasmic-side term rather than imply a transmembrane topology. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982017 | MODIFY | Summary: RGS4 acts on membrane-associated G alpha from the cytoplasmic face. Reason: Refine the broad plasma-membrane annotation to the separately retained cytoplasmic-side term rather than imply a transmembrane topology. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982019 | MODIFY | Summary: RGS4 acts on membrane-associated G alpha from the cytoplasmic face. Reason: Refine the broad plasma-membrane annotation to the separately retained cytoplasmic-side term rather than imply a transmembrane topology. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982020 | MODIFY | Summary: RGS4 acts on membrane-associated G alpha from the cytoplasmic face. Reason: Refine the broad plasma-membrane annotation to the separately retained cytoplasmic-side term rather than imply a transmembrane topology. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982025 | MODIFY | Summary: RGS4 acts on membrane-associated G alpha from the cytoplasmic face. Reason: Refine the broad plasma-membrane annotation to the separately retained cytoplasmic-side term rather than imply a transmembrane topology. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982026 | MODIFY | Summary: RGS4 acts on membrane-associated G alpha from the cytoplasmic face. Reason: Refine the broad plasma-membrane annotation to the separately retained cytoplasmic-side term rather than imply a transmembrane topology. Proposed replacements: cytoplasmic side of plasma membrane Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS Reactome:R-HSA-388396 | ACCEPT | Summary: The RGS4 GAP mechanism directly terminates receptor-activated Gi/o and Gq signaling at the intracellular membrane surface. Reason: Purified-protein and receptor-current experiments support this core function; it need not be the dominant regulator of every native receptor. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | TAS PMID:10747990 Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trispho... | MODIFY | Summary: The established RGS4 role is negative regulation through accelerated G alpha inactivation. Reason: Refine to the existing negative-regulation term. Proposed replacements: negative regulation of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:0009898 cytoplasmic side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The RGS4 GAP mechanism directly terminates receptor-activated Gi/o and Gq signaling at the intracellular membrane surface. Reason: Purified-protein and receptor-current experiments support this core function; it need not be the dominant regulator of every native receptor. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:0010460 positive regulation of heart rate | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The RGS4-selective inhibitor study potentiated muscarinic bradycardia, supporting an RGS4-dependent restraint of the heart-rate-lowering response. Reason: Retain this conditional positive heart-rate regulation; it does not imply that RGS4 replaces the predominant native RGS6–GNB5 cardiac mechanism. |
| GO:0019901 protein kinase binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The traced rat study PMID:17084383 shows co-immunoprecipitation of RGS4 in a CASK-associated signaling complex. Reason: That supports association with a kinase-containing assembly but the accessible text does not establish a direct binary kinase-binding interaction. The precise binding claim remains unresolved pending target-level interaction mapping. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P49799 UNRESOLVED The traced rat study PMID:17084383 shows co-immunoprecipitation of RGS4 in a CASK-associated signaling complex. That supports association with a kinase-containing assembly but the accessible text does not establish a direct binary kinase-binding interaction. The precise binding claim remains unresolved pending target-level interaction mapping. Supporting Evidence: |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | ACCEPT | Summary: The experimentally resolved RGS4–Gi1–MgGDP–AlF4 assembly establishes physical complex formation. Reason: Its transition-state nature does not warrant guessing membership in a constitutive receptor complex; the broad complex term is retained at the demonstrated level. Supporting Evidence: PMID:9108480 The core domain binds to the three switch regions of G(i alpha1) |
| GO:0042220 response to cocaine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Chronic cocaine and subsequent abstinence reduce rat RGS4 transcript levels, with restoration after context re-exposure. Reason: This supports a contextual response annotation, not a primary cocaine-processing function. Supporting Evidence: |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat prefrontal RGS4 mRNA and protein rise after chronic intermittent ethanol and withdrawal. Reason: The transferred response term is retained with that experimental scope. Supporting Evidence: |
| GO:0045744 negative regulation of G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The RGS4 GAP mechanism directly terminates receptor-activated Gi/o and Gq signaling at the intracellular membrane surface. Reason: Purified-protein and receptor-current experiments support this core function; it need not be the dominant regulator of every native receptor. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:0045744 negative regulation of G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: The RGS4 GAP mechanism directly terminates receptor-activated Gi/o and Gq signaling at the intracellular membrane surface. Reason: Purified-protein and receptor-current experiments support this core function; it need not be the dominant regulator of every native receptor. Supporting Evidence: PMID:8756726 accelerating the rate of GTP hydrolysis by Gi alpha 1 at least 40-fold PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:0051924 regulation of calcium ion transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: In dopamine-depleted striatal cholinergic interneurons, increased RGS4 attenuates M4 autoreceptor control of calcium channels. Reason: This is regulation of calcium transport through receptor signaling, not direct calcium-channel pore activity. Supporting Evidence: |
| GO:0060160 negative regulation of dopamine receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RGS4 coexpression inhibits D2/D3 receptor signaling through its N-terminal interaction region in HEK293 assays. Reason: Retain this receptor-selective regulatory function without asserting equal activity toward all dopamine receptors; D4 was unaffected in a separate cortical experiment. |
| GO:0061052 negative regulation of cell growth involved in cardiac muscle cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RGS4 expression in cultured cardiomyocytes blocks agonist-driven growth and myofilament organization; a GAP-defective mutant fails to block the transcriptional response. Reason: These are contextual downstream consequences of its active signaling-regulator role, not intrinsic actin-remodeling catalysis. Supporting Evidence: |
| GO:0110053 regulation of actin filament organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RGS4 expression in cultured cardiomyocytes blocks agonist-driven growth and myofilament organization; a GAP-defective mutant fails to block the transcriptional response. Reason: These are contextual downstream consequences of its active signaling-regulator role, not intrinsic actin-remodeling catalysis. Supporting Evidence: |
| GO:1900924 negative regulation of glycine import across plasma membrane | IEA GO_REF:0000107 | UNDECIDED | Summary: The donor study PMID:21798518 reports modulation of glycine-evoked patch-clamp currents, while GO:1900924 requires reduced glycine import into the cell. Reason: Glycine-receptor current and amino-acid uptake are distinct endpoints. Full target-level results and independent uptake measurements were not recovered, so the transferred uptake claim remains unresolved rather than accepted from the current assay. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P49799 UNRESOLVED The donor study PMID:21798518 reports modulation of glycine-evoked patch-clamp currents, while GO:1900924 requires reduced glycine import into the cell. Glycine-receptor current and amino-acid uptake are distinct endpoints. Full target-level results and independent uptake measurements were not recovered, so the transferred uptake claim remains unresolved rather than accepted from the current assay. Supporting Evidence: PMID:21798518 using immunohistochemistry, Western blot analysis and whole-cell patch-clamp techniques |
| GO:1901379 regulation of potassium ion transmembrane transport | IEA GO_REF:0000107 | MODIFY | Summary: RGS4 regulates M2-gated potassium currents, and PMID:24421355 specifically demonstrates inhibitory control of pilocarpine-mediated currents. Reason: Refine the unsigned transport-regulation term to the already asserted negative term; the older developmental-expression source alone is not a channel assay. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:P49799 SUPPORTS TRANSFER RGS4 regulates M2-gated potassium currents, and PMID:24421355 specifically demonstrates inhibitory control of pilocarpine-mediated currents. Refine the unsigned transport-regulation term to the already asserted negative term; the older developmental-expression source alone is not a channel assay. Proposed replacements: negative regulation of potassium ion transmembrane transport Supporting Evidence: PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:1901380 negative regulation of potassium ion transmembrane transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat atrial and Xenopus reconstitution experiments demonstrate RGS4-dependent suppression of M2–G protein activation of inwardly rectifying potassium currents, especially for the partial agonist pilocarpine. Reason: Retain this conditional channel-regulatory role. Supporting Evidence: PMID:24421355 pilocarpine acted as a partial agonist in the presence of RGS4 |
| GO:1990791 dorsal root ganglion development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The traced rat source PMID:14550772 establishes adult sensory-neuron expression, regulation by GDNF and injury-induced downregulation. Reason: Those observations do not establish that RGS4 executes dorsal-root-ganglion development. The developmental transfer exceeds the source endpoint; an undiscovered developmental role is not excluded. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:P49799 UNRESOLVED The traced rat source PMID:14550772 establishes adult sensory-neuron expression, regulation by GDNF and injury-induced downregulation. Those observations do not establish that RGS4 executes dorsal-root-ganglion development. The developmental transfer exceeds the source endpoint; an undiscovered developmental role is not excluded. Supporting Evidence: |
| GO:2000463 positive regulation of excitatory postsynaptic potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RGS4 attenuates 5-HT1A-dependent suppression of NMDA receptor current in rat prefrontal pyramidal neurons. Reason: This disinhibitory mechanism supports increased excitatory postsynaptic responses in that context, without making RGS4 an excitatory receptor or universal positive synaptic regulator. Supporting Evidence: |
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Q: Which components mediate the RGS4–CASK association, and is binary kinase binding demonstrable?
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