Affinage

RGS4

Regulator of G-protein signaling 4 · UniProt P49798

Length
205 aa
Mass
23.3 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS4 is a GTPase-activating protein (GAP) that negatively regulates G protein-coupled receptor signaling by accelerating GTP hydrolysis on Gi/o- and Gq-family Galpha subunits, thereby terminating signaling at the level of the heterotrimeric G protein (PMID:8756726, PMID:9012799). It functions catalytically rather than as an effector: it binds with high affinity to the transition-state (GDP-AlF4-) conformation of Galpha and accelerates hydrolysis at least 40-fold by stabilizing the switch-region conformation rather than contributing catalytic residues, as established biochemically and by the crystal structure of the RGS4 core domain bound to Gialpha1 (PMID:8756726, PMID:8910288, PMID:9108480, PMID:9430692). The conserved ~120-residue RGS domain is sufficient for GAP activity toward Gi-class substrates (PMID:9207071), and against Gq RGS4 additionally occludes the effector-binding surface to block phospholipase C-beta activation (PMID:9012799, PMID:9115254). The N-terminal domain confers receptor selectivity and high potency: it forms an amphipathic alpha-helix that anchors RGS4 to anionic phospholipids of the plasma membrane—localization required for function in vivo—and enables direct precoupling to GPCR-channel macromolecular complexes, accounting for ~10,000-fold higher potency than the isolated RGS box (PMID:9856989, PMID:9576926, PMID:10764749, PMID:16973624). RGS4 activity and abundance are tightly regulated: PKA/PKG phosphorylation at Ser-52 drives membrane translocation and enhances GAP activity (PMID:16885398); PtdIns(3,4,5)P3 and Ca2+/calmodulin reciprocally modulate the RGS domain (PMID:15324308); and RGS4 is a physiological N-end rule substrate degraded after Met excision, Cys-2 arginylation by ATE1, and UBR1/UBR2-dependent ubiquitination, a route gated by hypoxia and nitric oxide (PMID:10783390, PMID:16217033, PMID:23454748). Through these mechanisms RGS4 sets the gain of GPCR signaling in defined physiological contexts, including parasympathetic control of sinoatrial rhythm and GIRK/IKACh kinetics (PMID:18658048), atrial Galphaq/IP3 calcium handling (PMID:26088132), cardiomyocyte hypertrophic signaling (PMID:9918533, PMID:11162127, PMID:23454748), pancreatic beta-cell M3R-dependent insulin secretion (PMID:20385802), and striatal indirect-pathway endocannabinoid LTD relevant to Parkinsonian motor deficits (PMID:22284188).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Established that RGS4 is an enzyme that terminates G protein signaling by accelerating GTP hydrolysis, defining RGS proteins as GAPs for heterotrimeric Galpha and explaining a key off-switch for GPCR signaling.

    Evidence In vitro GTPase and transition-state binding assays with purified Gi/o alpha subunits

    PMID:8756726 PMID:8910288

    Open questions at the time
    • Did not resolve the structural basis of acceleration
    • Selectivity across Gq vs Gi families not yet defined in vivo
  2. 1997 High

    Resolved how RGS4 accelerates hydrolysis—by conformationally stabilizing the three Galpha switch regions rather than supplying catalytic residues—and extended substrate range to Gq with effector-site occlusion as an added inhibitory mechanism.

    Evidence 2.8 A crystal structure of RGS4-Gialpha1-GDP-AlF4-, plus PLC-beta and MAPK/phosphoinositide assays for Gq, and RGS-domain deletion mapping

    PMID:9012799 PMID:9108480 PMID:9115254 PMID:9177187 PMID:9207071

    Open questions at the time
    • Did not explain receptor selectivity observed in cells
    • Role of the N-terminal domain beyond the RGS box unaddressed
  3. 1998 High

    Identified the N-terminal domain as the determinant of receptor-selective, high-potency inhibition and a membrane-anchoring module required for function, separating catalytic chemistry from cellular targeting.

    Evidence In vitro reconstitution, deletion/cysteine mutagenesis, yeast functional and GFP-localization assays, and neuronal/oocyte electrophysiology

    PMID:9430692 PMID:9437012 PMID:9576926 PMID:9856989

    Open questions at the time
    • Biophysical basis of membrane binding not yet defined
    • Palmitoylation role in mammalian targeting unresolved
  4. 2000 High

    Defined the membrane-binding mechanism as an amphipathic helix engaging anionic phospholipids and confirmed that this localization is required for biological activity, while NMR revealed an induced-fit conformational change on Galpha binding.

    Evidence Liposome co-sedimentation, circular dichroism, NMR solution structure, and yeast functional mutagenesis

    PMID:10764749 PMID:10852703

    Open questions at the time
    • How membrane binding integrates with receptor precoupling not yet shown
  5. 1999 High

    Showed RGS4 abundance and activity are post-translationally tuned, with autopalmitoylation at Cys-95 and N-terminal cysteines context-dependently modulating GAP activity.

    Evidence [3H]palmitate labeling, in vitro autopalmitoylation, and single-turnover/proteoliposome GTPase assays

    PMID:10608901

    Open questions at the time
    • Physiological enzyme/regulator of palmitoylation not identified
    • Opposite effects in solution vs proteoliposomes unreconciled
  6. 2005 High

    Established RGS4 as a bona fide in vivo N-end rule substrate, defining a regulated degradation route (Cys-2 arginylation by ATE1, UBR1/UBR2 ubiquitination) that links RGS4 levels to oxygen and signaling state.

    Evidence ATE1- and UBR1/UBR2-knockout systems, in vivo pulse-chase, and Cys-2 mutagenesis; reciprocal PIP3/Ca-CaM binding by SPR and co-sedimentation

    PMID:10783390 PMID:15324308 PMID:16217033

    Open questions at the time
    • Upstream signals controlling Cys-2 oxidation in cells incompletely defined
    • Quantitative contribution of degradation to physiological signaling unclear
  7. 2006 High

    Defined kinase control and the precoupling mode of action: PKA/PKG phosphorylation at Ser-52 drives membrane translocation and enhanced GAP activity, and direct assembly with GPCR-Kir3 complexes confers ~100-fold potency over collision coupling.

    Evidence Site-directed S52A mutagenesis with fractionation and GTPase/PI assays; co-IP and oocyte electrophysiology with domain-mapped RGS constructs

    PMID:16885398 PMID:16973624

    Open questions at the time
    • Stoichiometry and structure of the precoupled complex not resolved
    • Generality of Ser-52 phosphorylation across tissues not established
  8. 2008 High

    Demonstrated a physiological role in cardiac rhythm: RGS4 restrains parasympathetic Gi/o signaling at the sinoatrial node, shaping baseline heart rate and GIRK/IKACh kinetics.

    Evidence RGS4-null mice with in vivo telemetry, perfused-heart, and SAN myocyte patch-clamp

    PMID:18658048

    Open questions at the time
    • Receptor specificity at the SAN not fully dissected
    • Compensation by other RGS proteins not excluded
  9. 2012 High

    Placed RGS4 in CNS circuit physiology, linking D2/A2A-cAMP/PKA signaling to endocannabinoid mobilization and indirect-pathway LTD, with loss-of-function rescuing motor deficits in a Parkinson's model.

    Evidence RGS4-knockout mice, striatal LTD electrophysiology, and 6-OHDA lesion behavioral analysis; neurabin-A1R scaffolding co-IP and seizure models

    PMID:22284188 PMID:22357852

    Open questions at the time
    • Direct Galpha substrate in MSNs not isolated in vivo
    • Therapeutic window of RGS4 inhibition not defined
  10. 2013 High

    Connected RGS4 turnover to disease-relevant cardiomyocyte growth, showing NO-induced proteasomal degradation of RGS4 derepresses Gbeta-gamma/PI3Kgamma/AKT/mTORC1 hypertrophic signaling, with trafficking through Rab5/Rab11 endosomal routes setting membrane availability.

    Evidence PlGF transgenic, eNOS-knockout, and cardiac RGS4-overexpression mice with NOS inhibition; Rab5/Rab11 dominant-negative/active mutants with M1R/Gq functional assays

    PMID:23454748 PMID:23733193

    Open questions at the time
    • Molecular trigger coupling NO to RGS4 degradation not fully defined
    • Direct E3 machinery in cardiomyocytes not identified
  11. 2015 High

    Extended cardiac function to atrial arrhythmia, showing RGS4 loss enhances Galphaq/11-IP3 calcium release and predisposes to atrial fibrillation.

    Evidence RGS4 global-knockout mice with atrial burst pacing and confocal Ca2+ spark imaging

    PMID:26088132

    Open questions at the time
    • Receptor upstream of atrial Gq not specified
    • Translation to human atrial fibrillation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RGS4's multiple regulatory layers—phosphorylation, lipid/Ca2+-CaM modulation, palmitoylation, N-end rule degradation, and Rab-dependent trafficking—are integrated in real time to set receptor-selective signaling gain in a given cell type.
  • No unified quantitative model linking RGS4 modification state to membrane residence and GAP output
  • Endogenous receptor-RGS4 complex composition in native tissues undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-397014 Muscle contraction 4 R-HSA-112316 Neuronal System 3 R-HSA-392499 Metabolism of proteins 2
Partners
ATE1F2RGNAI1GNAO1GNAQOPRD1PPP1R9AUBR1
Complex memberships
GPCR-Kir3 (GIRK) channel precoupling complexneurabin-A1R-RGS4 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 RGS4 is a GTPase-activating protein (GAP) that accelerates GTP hydrolysis by Gi alpha subunits at least 40-fold in vitro; all Gi subfamily members tested were substrates, but Gs alpha was not. In vitro GTPase assay with purified recombinant proteins Cell High 8756726
1996 RGS4 stabilizes the transition state for GTP hydrolysis, binding with high affinity to GDP-AlF4--bound forms of Goalpha and Gialpha (transition-state analogues) but with low affinity to GTPgammaS- and GDP-bound forms, indicating a catalytic rather than effector role. In vitro GTPase assay, transition-state binding experiments with purified recombinant RGS4 The Journal of biological chemistry High 8910288
1997 Crystal structure of RGS4 core domain bound to Gialpha1-Mg2+-GDP-AlF4- at 2.8 Å resolution reveals that RGS4 binds the three switch regions of Gialpha1 but contributes no catalytic residues directly contacting GDP or AlF4-; it accelerates GTP hydrolysis primarily by stabilizing the switch region conformation, with Asn-128 potentially interacting with the hydrolytic water. X-ray crystallography (2.8 Å resolution crystal structure) Cell High 9108480
1997 RGS4 and GAIP act as GAPs for Gq alpha, blocking activation of phospholipase C beta by GTPgammaS-Gq alpha; the blockade of PLC beta results from occlusion of the effector binding site on Galpha, not solely from GAP activity. In vitro GTPase assay and PLC beta activation assay with purified proteins and plasma membranes Proceedings of the National Academy of Sciences of the United States of America High 9012799
1997 The conserved 120-amino acid RGS domain of RGS4 is sufficient for GTPase-accelerating activity toward Gi class substrates (Gialpha1, Goalpha, Gzalpha) in vitro; short deletions within the RGS domain of RGS4 destroyed GAP activity and Gialpha1 binding. In vitro GTPase assay, surface plasmon resonance binding, deletion mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 9207071
1997 RGS4 inhibits Gq/11-mediated activation of MAPK and phosphoinositide synthesis in COS-7 cells; it competes for effector binding on Galphaq as well as acting as a GAP, demonstrated by inhibition even with AlF4--activated recombinant alphaq. Transient transfection in COS-7 cells, MAPK activation assay, inositol phosphate synthesis assay The Journal of biological chemistry High 9115254
1997 Stable expression of RGS4 in mammalian cells attenuates both Gi-mediated inhibition of cAMP synthesis and Gq-mediated activation of phospholipase C beta, confirming in vivo GAP activity consistent with in vitro selectivity. Stable transfection in mammalian cells, cAMP assay, phospholipase C assay Proceedings of the National Academy of Sciences of the United States of America High 9177187
1998 The N-terminal domain (first ~33 amino acids) of RGS4 confers receptor-selective inhibition of Gq-coupled signaling and is required for high-potency GAP activity; deletion of this domain eliminates receptor selectivity and reduces potency ~10,000-fold; in vitro reconstitution confirmed that both the RGS box and N-terminal flanking sequences are required for high potency. In vitro reconstitution, deletion mutagenesis, Xenopus oocyte and cell-based signaling assays The Journal of biological chemistry High 9856989
1998 GAP activity of RGS4 requires the additive effects of multiple residues along the RGS4-Galpha interface that stabilize the Galpha transition-state conformation; Asn-128 is not exclusively required for catalysis, showing RGS4 acts by conformational stabilization rather than direct chemistry. Mutational analysis combined with biochemical GTPase assays and binding measurements The Journal of biological chemistry High 9430692
1998 Plasma membrane localization of RGS4 is required for its in vivo function in inhibiting pheromone signaling in yeast; the N-terminal 33 amino acids constitute a plasma membrane anchorage domain sufficient to localize an otherwise soluble protein to the membrane; RGS4 is palmitoylated at Cys-2 and Cys-12, but palmitoylation of these residues is not required for membrane targeting in yeast. Yeast functional assay, GFP fusion localization, deletion and cysteine mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 9576926
1998 RGS4 inhibits group I metabotropic glutamate receptor (mGluR1a, mGluR5a)-mediated activation of calcium-dependent chloride current in Xenopus oocytes and attenuates mGluR5-mediated inhibition of potassium currents in hippocampal CA1 neurons. Xenopus oocyte electrophysiology with purified RGS4 microinjection; hippocampal neuron patch-clamp The Journal of neuroscience High 9437012
1998 GTPase-deficient Gialpha2 (Q204L) expression recruits cytoplasmic RGS4 to the plasma membrane, and this occurs even with a non-Gialpha-binding RGS4 mutant (L159F), suggesting indirect recruitment through G-protein activation rather than direct RGS4-Galpha binding. Subcellular fractionation and immunofluorescence in transfected cells; expression of constitutively active Galpha mutant The Journal of biological chemistry Medium 9660808
1999 RGS4 is palmitoylated at a conserved Cys-95 within the RGS domain (autopalmitoylation with palmitoyl-CoA) as well as at Cys-2/Cys-12 at the N-terminus; palmitoylation of Cys-95 inhibits GAP activity 80–100% in solution-based assays but potentiates activity in receptor-G protein proteoliposomes. [3H]palmitate labeling in Sf9 cells, autopalmitoylation assay in vitro, single-turnover and steady-state GTPase assays The Journal of biological chemistry High 10608901
1999 RGS4 inhibits G-protein-mediated signaling in cardiomyocytes: overexpression blocks phenylephrine- and endothelin-1-mediated gene induction (ANF, MLC-2) and myofilament organization; a GAP-defective point mutant (N128A-RGS4) fails to inhibit, establishing that GAP activity is required. Cardiomyocyte transfection, reporter gene assay, N128A point mutant control Circulation High 9918533
2000 RGS4 is an N-end rule substrate: its N-terminal methionine is removed to expose Cys-2, which is arginylated, making N-terminal Arg the degradation signal; converting Cys-2 to Gly, Ala, or Val completely stabilized RGS4 in reticulocyte lysate. Expression-cloning screen in reticulocyte lysate, radiochemical N-terminal sequencing, mutagenesis, pulse-chase degradation assay The Journal of biological chemistry High 10783390
2000 NMR solution structure of free RGS4 reveals an induced conformational change upon binding Gialpha1; the Galpha-binding site is larger and more open in free RGS4, with a kink in the helix (K116-Y119) becoming more pronounced upon binding, enabling hydrogen-bonding to Gialpha1 residues. 2D/3D heteronuclear NMR spectroscopy (30 structures calculated with 2871 restraints) Biochemistry High 10852703
2000 The N-terminal domain of RGS4 mediates membrane binding through an amphipathic alpha-helix that interacts with anionic phospholipids via hydrophobic and electrostatic interactions; point mutations neutralizing positive charges or substituting polar residues on the hydrophobic face disrupt membrane targeting and biological activity. Liposome co-sedimentation, circular dichroism spectroscopy of peptide, mutagenesis in yeast functional assay The Journal of biological chemistry High 10764749
2000 RGS4 selectively enhances alpha2A-adrenoreceptor stimulation of GTPase activity of Galpha-o1 and Galpha-i2, but not Galpha-i1 or Galpha-i3; this selectivity resides in the receptor-G protein context; RGS4 increases both Vmax and Km for GTP. GTPase activity assay using receptor-Galpha fusion proteins transiently expressed in COS-7 cells; enzyme kinetic analysis The Journal of biological chemistry Medium 10807934
2000 RGS4 binds the COPI subunit beta'-COP through two dilysine motifs, co-fractionates with the COPI complex, inhibits COPI association with Golgi membranes, and impairs vesicular trafficking (aquaporin-1 and alkaline phosphatase secretion) independently of its GAP activity. Yeast two-hybrid, in vitro binding with purified proteins, co-fractionation by gel filtration, immunofluorescence, trafficking assays in transfected cells Molecular biology of the cell Medium 10982407
2001 The RGS domain of RGS4 and its interaction with pertussis toxin-sensitive Galpha subunits mediates voltage-dependent relaxation of G protein-gated inwardly rectifying K+ (KG/Kir3) channels; RGS domain mutations that impair Galpha binding abolish the relaxation effect. Xenopus oocyte electrophysiology, expression of RGS4 deletion and point mutants The Journal of physiology High 11507164
2001 Cardiac-specific expression of RGS4 in transgenic mice reduces Galphaq-induced contractile dysfunction and hypertrophic gene induction (PKC-xi membrane translocation, ANF, alpha-skeletal actin mRNA), establishing RGS4 as an in vivo GAP for Galphaq in the heart. Dual transgenic mouse model (Galphaq-40 × RGS4), echocardiography, gene expression analysis Journal of molecular and cellular cardiology High 11162127
2003 GFP-tagged RGS4 expressed in HEK293 cells localizes to cytosol but is selectively recruited to the plasma membrane by co-expression of Galphai2 or M2 muscarinic receptor; G protein mutants with reduced RGS affinity fail to recruit RGS4, indicating the recruitment involves direct binding. GFP fusion protein localization in HEK293 cells, co-expression with G protein and receptor mutants, GTPase activity assay Molecular pharmacology Medium 12920194
2005 RGS4 and RGS5 are in vivo substrates of the N-end rule pathway: ATE1 Arg-transferase mediates arginylation of N-terminal Cys-2 (after methionine excision), targeting them for ubiquitin-dependent proteasomal degradation via UBR1/UBR2 E3 ligases; mutant RGS4 with Cys-2 unable to become N-terminal is long-lived in vivo; hypoxia perturbs this proteolysis. ATE1-knockout mouse analysis, UBR1/UBR2 knockout cells, in vivo pulse-chase, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 16217033
2005 PtdIns(3,4,5)P3 and Ca2+/calmodulin competitively bind to the RGS domain of RGS4 at a cluster of positively charged residues on the surface opposite the Galpha interaction site, reciprocally regulating GAP activity; Ca2+/CaM binding relieves PtdIns(3,4,5)P3-mediated inhibition of GAP activity. Lipid-protein co-sedimentation assay, surface plasmon resonance, mutagenesis The Biochemical journal High 15324308
2005 RGS4 directly interacts with C-terminal domains of both mu- and delta-opioid receptors and with the third intracellular loop of the delta-opioid receptor via GST pulldown; RGS4 modulates mu-OR signaling and can form stable heterotrimeric complexes with activated Galpha. GST fusion protein pulldown, co-immunoprecipitation, cell signaling assay Cellular signalling Medium 16120478
2006 PKA and PKG phosphorylate RGS4 at Ser-52, inducing its translocation from cytosol to plasma membrane and enhancing its association with Galphaq.GTP and intrinsic GTPase activity; expression of RGS4(S52A) blocks kinase-mediated increases in GTPase activity and inhibition of PI hydrolysis. In vitro phosphorylation assay, subcellular fractionation, co-immunoprecipitation, GTPase activity assay, PI hydrolysis assay in smooth muscle cells with S52A mutant American journal of physiology. Cell physiology High 16885398
2006 RGS4 directly associates with multiple GPCR-Kir3 channel complexes (precoupling mode) through both its N-terminal domain and RGS domain, conferring 100-fold greater potency in accelerating G protein-dependent Kir3 channel-gating kinetics compared to the collision-coupling mode of RGS3s. Co-immunoprecipitation of epitope-tagged proteins in CHO-K1 cells, Xenopus oocyte electrophysiology, deletion/chimeric RGS constructs The Journal of biological chemistry High 16973624
2006 RGS4 and GABA(B) R1/R2 subunits are within 100 Å of each other in the plasma membrane as measured by FRET (~13% FRET efficiency), consistent with their association in a signaling complex with Galphao and Kir3 channels. FRET combined with total internal reflection fluorescence microscopy in HEK293 cells The Journal of physiology Medium 17185339
2007 The small molecule CCG-4986 inhibits RGS4 by covalently modifying Cys-132 within the RGS domain on the Galpha-interaction face, causing steric hindrance; sensitivity to CCG-4986 requires Cys-132 and can be introduced into RGS8 by substituting the equivalent residue to cysteine. Surface plasmon resonance, FRET assay, single-turnover GTP hydrolysis, mass spectrometry, site-directed mutagenesis Biochimica et biophysica acta High 17660054
2008 RGS4-null mice show enhanced bradycardic responses to parasympathetic agonists, lower baseline heart rates, and decreased GIRK channel desensitization in sinoatrial node myocytes, establishing that RGS4 regulates sinus rhythm by inhibiting parasympathetic (Gi/o) signaling and IKACh activity. RGS4 knockout mouse model, in vivo telemetry, retrograde-perfused heart, SAN myocyte patch-clamp Circulation research High 18658048
2008 IL-1beta upregulates RGS4 expression in colonic smooth muscle via the canonical IKK2/IkappaBalpha/NF-kappaB pathway; siRNA knockdown of RGS4 blocks IL-1beta inhibition of initial contraction and PLC-beta activation, establishing RGS4 as an NF-kappaB target gene mediating IL-1beta effects. siRNA knockdown, reporter luciferase assay, NF-kappaB-DNA binding, IkappaBalpha degradation, kinase-inactive mutant expression, smooth muscle contraction assay The Biochemical journal High 18260825
2009 RGS4 selectively modulates delta-opioid receptor (DOR) signaling but not mu-opioid receptor signaling in SH-SY5Y cells; co-immunoprecipitation with a stable RGS4 mutant showed interaction with delta-OR but not mu-OR; the C-tail and third intracellular domain of delta-OR are the interaction sites. Stable shRNA knockdown (~90% reduction), co-immunoprecipitation, receptor chimeras, cAMP assay, MAPK assay The Journal of biological chemistry High 19416973
2010 RGS4 is the dominant RGS protein in pancreatic beta-cell MIN6 insulinoma cells; siRNA-mediated knockdown of RGS4 greatly enhances M3 muscarinic receptor-mediated augmentation of glucose-stimulated insulin secretion (GSIS) and calcium release; beta-cell-specific RGS4 deletion increases muscarinic agonist-induced insulin release in vivo. siRNA knockdown in MIN6 cells, calcium imaging, insulin secretion assay, conditional beta-cell-specific knockout mice, in vivo plasma insulin measurement Proceedings of the National Academy of Sciences of the United States of America High 20385802
2011 Opioid agonist exposure leads to ubiquitination and proteasomal/lysosomal degradation of RGS4 protein in SH-SY5Y cells; this is Gi/o-dependent (blocked by pertussis toxin), reduces RGS4 ~60%, and subsequent cross-talk between delta-OR and M3 muscarinic receptor signaling depends on this RGS4 reduction. Proteasome inhibitors (MG132, lactacystin), polyubiquitination detection, pertussis toxin treatment, signaling assays The Journal of biological chemistry Medium 21209077
2012 RGS4 is identified as a key link between D2/A2A receptor cAMP/PKA signaling and endocannabinoid mobilization in striatal indirect-pathway MSNs; RGS4-null mice exhibit preserved eCB-LTD after dopamine depletion and significantly reduced motor impairment in the 6-OHDA Parkinson's disease model. RGS4 knockout mice, electrophysiology (LTD measurements), 6-OHDA lesion model, pharmacological dissection Neuron High 22284188
2012 Neurabin scaffolds adenosine A1 receptor and RGS4 into a complex; disruption of this complex (neurabin knockout or RGS4 inhibitor) enhances A1R signaling and protects against excitotoxic seizure, demonstrating that neurabin-RGS4 assembly attenuates A1R-mediated neuroprotection. Co-immunoprecipitation, neurabin-null mice, RGS4 inhibitor administration, kainate seizure model, neuronal death assay The Journal of neuroscience High 22357852
2013 NO production (from endothelial-derived eNOS) induces proteasomal degradation of RGS4, relieving repression of the Gbeta-gamma/PI3Kgamma/AKT/mTORC1 pathway and stimulating cardiomyocyte growth; cardiac-specific RGS4 transgenic overexpression prevents this hypertrophy, and eNOS knockout blocks it. PlGF transgenic mice, eNOS knockout mice, cardiac-specific RGS4 transgenic overexpression, NOS inhibitor L-NAME, Western blot for RGS4 and AKT/mTORC1 signaling The Journal of clinical investigation High 23454748
2013 Rab5 and Rab11 regulate RGS4 intracellular trafficking: constitutively active Rab5 decreases RGS4 plasma membrane levels and increases endosomal targeting; dominant-negative Rab11 traps RGS4 in endosomes and decreases its function as inhibitor of M1R/Gq signaling; Cys-12 of RGS4 is important for Rab11-mediated recycling to the plasma membrane. Constitutively active/dominant-negative Rab GTPase expression, co-localization with endosomal markers, functional M1R/Gq signaling assay The Journal of biological chemistry Medium 23733193
2014 RGS4 interacts with the third intracellular loop of PAR1 directly (purified protein binding) and in live cells (BRET), in a Galpha-o-dependent manner (Galphao but not other Galpha promotes PAR1-RGS4 BRET); RGS4 inhibits PAR1/Galpha-mediated MAPK/ERK signaling but not RhoA signaling. BRET in COS-7 cells, GST pulldown with purified proteins, PAR1 mutants, signaling assays PloS one Medium 24743392
2015 Deletion of RGS4 predisposes mice to atrial fibrillation; RGS4-null atrial cells show increased Ca2+ spark frequency and abnormal Ca2+ release events under basal conditions and after endothelin-1, attributable to enhanced Galphaq/11-IP3 pathway activity. RGS4 global knockout mice, in vivo atrial burst pacing electrophysiology, confocal Ca2+ spark imaging, multielectrode array The Journal of biological chemistry High 26088132
2007 RGS4 expression is upregulated in colonic smooth muscle by IL-1beta; siRNA knockdown of RGS4 blocks IL-1beta-mediated inhibition of initial contraction and PLC-beta activation, and RGS4 overexpression inhibits PLC-beta activation. siRNA knockdown in muscle strips and cultured cells, overexpression, contraction assay, PLC-beta activation measurement American journal of physiology. Cell physiology Medium 17959727

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell 704 9108480
1996 GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Cell 677 8756726
2001 Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Molecular psychiatry 350 11326297
1997 RGS4 and GAIP are GTPase-activating proteins for Gq alpha and block activation of phospholipase C beta by gamma-thio-GTP-Gq alpha. Proceedings of the National Academy of Sciences of the United States of America 330 9012799
1996 The GTPase-activating protein RGS4 stabilizes the transition state for nucleotide hydrolysis. The Journal of biological chemistry 295 8910288
2002 Association and linkage analyses of RGS4 polymorphisms in schizophrenia. Human molecular genetics 269 12023979
2005 RGS4 and RGS5 are in vivo substrates of the N-end rule pathway. Proceedings of the National Academy of Sciences of the United States of America 230 16217033
1998 The N-terminal domain of RGS4 confers receptor-selective inhibition of G protein signaling. The Journal of biological chemistry 212 9856989
1997 The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro. Proceedings of the National Academy of Sciences of the United States of America 155 9207071
1997 Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 149 9177187
2012 RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits. Neuron 148 22284188
2000 RGS4 is arginylated and degraded by the N-end rule pathway in vitro. The Journal of biological chemistry 137 10783390
1998 Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 130 9576926
1997 RGS4 inhibits Gq-mediated activation of mitogen-activated protein kinase and phosphoinositide synthesis. The Journal of biological chemistry 129 9115254
1998 RGS4 inhibits signaling by group I metabotropic glutamate receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 120 9437012
2003 Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Molecular pharmacology 114 12920194
1998 Mechanism of RGS4, a GTPase-activating protein for G protein alpha subunits. The Journal of biological chemistry 108 9430692
2000 RGS4 binds to membranes through an amphipathic alpha -helix. The Journal of biological chemistry 107 10764749
2006 Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay. Molecular pharmacology 105 17012620
2008 RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circulation research 103 18658048
2004 Support for RGS4 as a susceptibility gene for schizophrenia. Biological psychiatry 100 14732600
2002 Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure. Cardiovascular research 96 12176127
2006 Evidence for association of GABA(B) receptors with Kir3 channels and regulators of G protein signalling (RGS4) proteins. The Journal of physiology 95 17185339
1999 Palmitoylation of a conserved cysteine in the regulator of G protein signaling (RGS) domain modulates the GTPase-activating activity of RGS4 and RGS10. The Journal of biological chemistry 88 10608901
2005 Generation and characterization of Rgs4 mutant mice. Molecular and cellular biology 84 15870291
2000 Rapid kinetics of regulator of G-protein signaling (RGS)-mediated Galphai and Galphao deactivation. Galpha specificity of RGS4 AND RGS7. The Journal of biological chemistry 83 10942773
2007 Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 17301167
2005 Genetic polymorphisms of the RGS4 and dorsolateral prefrontal cortex morphometry among first episode schizophrenia patients. Molecular psychiatry 82 15381923
2005 Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling. Cellular signalling 81 16120478
1999 Region-specific regulation of RGS4 (Regulator of G-protein-signaling protein type 4) in brain by stress and glucocorticoids: in vivo and in vitro studies. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 10233999
2006 Regional alterations in RGS4 protein in schizophrenia. Synapse (New York, N.Y.) 78 16565965
2006 Making the case for a candidate vulnerability gene in schizophrenia: Convergent evidence for regulator of G-protein signaling 4 (RGS4). Biological psychiatry 77 16860780
2006 Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. Biological psychiatry 71 16631129
1998 Expression of GTPase-deficient Gialpha2 results in translocation of cytoplasmic RGS4 to the plasma membrane. The Journal of biological chemistry 70 9660808
1999 RGS4 inhibits G-protein signaling in cardiomyocytes. Circulation 69 9918533
2013 NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. The Journal of clinical investigation 68 23454748
2006 Inhibition of Galphaq-dependent PLC-beta1 activity by PKG and PKA is mediated by phosphorylation of RGS4 and GRK2. American journal of physiology. Cell physiology 68 16885398
2010 RGS4 is a negative regulator of insulin release from pancreatic beta-cells in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 67 20385802
2004 Regulators of G-protein signaling 3 and 4 (RGS3, RGS4) are associated with glioma cell motility. Journal of neuropathology and experimental neurology 64 15055445
2000 Activation of extracellular signal-regulated kinase (ERK) and Akt by human serotonin 5-HT(1B) receptors in transfected BE(2)-C neuroblastoma cells is inhibited by RGS4. Journal of neurochemistry 64 10936173
2001 Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end-stage heart failure. European heart journal 63 11428836
2003 Differentially regulated expression of endogenous RGS4 and RGS7. The Journal of biological chemistry 61 14604980
1998 RGS3 and RGS4 are GTPase activating proteins in the heart. Journal of molecular and cellular cardiology 61 9515003
2004 Dopamine receptor-mediated regulation of RGS2 and RGS4 mRNA differentially depends on ascending dopamine projections and time. The European journal of neuroscience 56 15090051
2007 The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia. Genes, brain, and behavior 55 17410640
2004 Regional expression of RGS4 mRNA in human brain. The European journal of neuroscience 55 15182322
2004 Identification and characterization of regulator of G protein signaling 4 (RGS4) as a novel inhibitor of tubulogenesis: RGS4 inhibits mitogen-activated protein kinases and vascular endothelial growth factor signaling. Molecular biology of the cell 55 15548600
2001 RGS4 reduces contractile dysfunction and hypertrophic gene induction in Galpha q overexpressing mice. Journal of molecular and cellular cardiology 55 11162127
2000 The regulator of G protein signaling RGS4 selectively enhances alpha 2A-adreoreceptor stimulation of the GTPase activity of Go1alpha and Gi2alpha. The Journal of biological chemistry 55 10807934
2007 RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. Molecular pharmacology 54 17220354
2009 Differential modulation of mu- and delta-opioid receptor agonists by endogenous RGS4 protein in SH-SY5Y cells. The Journal of biological chemistry 50 19416973
2003 Dynamic expression of RGS4 in the developing nervous system and regulation by the neural type-specific transcription factor Phox2b. The Journal of neuroscience : the official journal of the Society for Neuroscience 50 14627646
2002 Expression of RGS2, RGS4 and RGS7 in the developing postnatal brain. The European journal of neuroscience 48 11906535
2007 Ethnic stratification of the association of RGS4 variants with antipsychotic treatment response in schizophrenia. Biological psychiatry 46 17588543
2007 The RGS protein inhibitor CCG-4986 is a covalent modifier of the RGS4 Galpha-interaction face. Biochimica et biophysica acta 46 17660054
2007 Upregulation of RGS4 and downregulation of CPI-17 mediate inhibition of colonic muscle contraction by interleukin-1beta. American journal of physiology. Cell physiology 45 17959727
2005 Phosphatidylinositol 3,4,5-trisphosphate and Ca2+/calmodulin competitively bind to the regulators of G-protein-signalling (RGS) domain of RGS4 and reciprocally regulate its action. The Biochemical journal 45 15324308
2006 RGS3 and RGS4 differentially associate with G protein-coupled receptor-Kir3 channel signaling complexes revealing two modes of RGS modulation. Precoupling and collision coupling. The Journal of biological chemistry 44 16973624
2005 Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil. Genes, brain, and behavior 43 15660667
2015 Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS chemical neuroscience 41 25844489
2006 Altered expression of regulator of G-protein signalling 4 (RGS4) mRNA in the superior temporal gyrus in schizophrenia. Schizophrenia research 41 17071056
2006 RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. Human molecular genetics 40 16905560
2002 Characterization and comparison of RGS2 and RGS4 as GTPase-activating proteins for m2 muscarinic receptor-stimulated G(i). Molecular pharmacology 39 12181442
2002 Opposite modulation of regulators of G protein signalling-2 RGS2 and RGS4 expression by dopamine receptors in the rat striatum. Neuroscience letters 39 12419501
2012 Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment. Oncogene 38 22562250
2020 Targeting RGS4 Ablates Glioblastoma Proliferation. International journal of molecular sciences 37 32392739
2019 lncRNA RPL34-AS1 inhibits cell proliferation and invasion while promoting apoptosis by competitively binding miR-3663-3p/RGS4 in papillary thyroid cancer. Journal of cellular physiology 37 31587286
1997 Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization. Biochemical and biophysical research communications 37 9425263
2009 Upregulation of RGS4 expression by IL-1beta in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3beta pathway. American journal of physiology. Cell physiology 36 19369446
2008 Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients. Biological psychiatry 36 19041089
2000 NMR structure of free RGS4 reveals an induced conformational change upon binding Galpha. Biochemistry 36 10852703
2012 Neurabin scaffolding of adenosine receptor and RGS4 regulates anti-seizure effect of endogenous adenosine. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 22357852
2008 Interleukin-1beta up-regulates RGS4 through the canonical IKK2/IkappaBalpha/NF-kappaB pathway in rabbit colonic smooth muscle. The Biochemical journal 35 18260825
2007 RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy. Journal of molecular and cellular cardiology 34 18207159
2005 Failure to confirm association between RGS4 haplotypes and schizophrenia in Caucasians. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 34 16082709
2001 Interaction between the RGS domain of RGS4 with G protein alpha subunits mediates the voltage-dependent relaxation of the G protein-gated potassium channel. The Journal of physiology 34 11507164
2001 Up-regulation of RGS4 mRNA by opioid receptor agonists in PC12 cells expressing cloned mu- or kappa-opioid receptors. European journal of pharmacology 34 11755131
2003 Differences in regional and subcellular localization of G(q/11) and RGS4 protein levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding parameters. Synapse (New York, N.Y.) 32 12422374
2013 RGS6, but not RGS4, is the dominant regulator of G protein signaling (RGS) modulator of the parasympathetic regulation of mouse heart rate. The Journal of biological chemistry 31 24318880
2012 An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma. PloS one 31 22253691
2008 RGS4 polymorphisms predict clinical manifestations and responses to risperidone treatment in patients with schizophrenia. Journal of clinical psychopharmacology 31 18204343
2006 Low mRNA levels of RGS4 splice variants in Alzheimer's disease: association between a rare haplotype and decreased mRNA expression. Synapse (New York, N.Y.) 31 16358332
2022 Bisphenol-A impairs synaptic formation and function by RGS4-mediated regulation of BDNF signaling in the cerebral cortex. Disease models & mechanisms 30 35781563
2012 Zebrafish rgs4 is essential for motility and axonogenesis mediated by Akt signaling. Cellular and molecular life sciences : CMLS 30 23052218
2005 Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia. Genes, brain, and behavior 30 16176390
2013 Rab family proteins regulate the endosomal trafficking and function of RGS4. The Journal of biological chemistry 29 23733193
2002 Endotoxin induces desensitization of cardiac endothelin-1 receptor signaling by increased expression of RGS4 and RGS16. Cardiovascular research 29 11744024
2011 RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling. Psychopharmacology 28 22193724
2009 Mapping the regulator of G protein signaling 4 (RGS4): presynaptic and postsynaptic substrates for neuroregulation in prefrontal cortex. Cerebral cortex (New York, N.Y. : 1991) 28 19153107
2004 Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors. The journal of peptide research : official journal of the American Peptide Society 28 15009535
2011 Opioid-induced down-regulation of RGS4: role of ubiquitination and implications for receptor cross-talk. The Journal of biological chemistry 27 21209077
2019 RGS4 Maintains Chronic Pain Symptoms in Rodent Models. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 31308097
2015 Intrathecal RGS4 inhibitor, CCG50014, reduces nociceptive responses and enhances opioid-mediated analgesic effects in the mouse formalin test. Anesthesia and analgesia 25 25695583
2015 Absence of the Regulator of G-protein Signaling, RGS4, Predisposes to Atrial Fibrillation and Is Associated with Abnormal Calcium Handling. The Journal of biological chemistry 25 26088132
2014 Regulator of G protein signaling 2 (RGS2) and RGS4 form distinct G protein-dependent complexes with protease activated-receptor 1 (PAR1) in live cells. PloS one 25 24743392
2011 RGS4, a GTPase activator, improves renal function in ischemia-reperfusion injury. Kidney international 25 21412219
2007 Full length cloning and expression analysis of splice variants of regulator of G-protein signaling RGS4 in human and murine brain. Gene 24 17707117
2006 Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4). American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 24 16508931
2006 Association study of the G-protein signaling 4 (RGS4) and proline dehydrogenase (PRODH) genes with schizophrenia: a meta-analysis. European journal of human genetics : EJHG 24 16791139
2000 RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport. Molecular biology of the cell 24 10982407

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