Affinage

RGS4

Regulator of G-protein signaling 4 · UniProt P49798

Length
205 aa
Mass
23.3 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS4 is a GTPase-activating protein (GAP) that accelerates GTP hydrolysis by Gαi and Gαq family subunits, thereby terminating heterotrimeric G protein signaling downstream of multiple GPCRs. Its RGS core domain binds the switch regions of activated Gα subunits and stabilizes the transition-state conformation without contributing catalytic residues directly to the hydrolysis site, while also occluding the effector-binding surface to antagonize phospholipase C-β activation (PMID:9108480, PMID:9012799). The N-terminal amphipathic domain confers receptor-selective inhibition, plasma membrane targeting, and direct interaction with GPCRs such as δ-opioid and GABAB receptors within pre-assembled receptor–Kir3 channel signaling complexes, and its protein levels are tightly controlled by sequential N-terminal Cys-2 oxidation, ATE1-mediated arginylation, and UBR1/UBR2-dependent proteasomal degradation via the N-end rule pathway (PMID:9856989, PMID:16973624, PMID:16217033). Through these mechanisms, RGS4 regulates cardiac parasympathetic pacemaking and hypertrophic signaling, striatal endocannabinoid-dependent synaptic plasticity, pancreatic β-cell insulin secretion, and smooth muscle contraction (PMID:18658048, PMID:22284188, PMID:20385802, PMID:18260825).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Establishing RGS4 as a GAP for Gi-family Gα subunits answered the fundamental question of what biochemical activity RGS proteins possess, revealing they accelerate GTP hydrolysis ≥40-fold and prefer the transition-state conformation of Gα.

    Evidence In vitro GTPase assays with purified recombinant proteins and AlF4⁻ transition-state trapping

    PMID:8756726 PMID:8910288

    Open questions at the time
    • Selectivity among Gi subfamily members not fully resolved
    • Mechanism of transition-state stabilization not yet structurally defined
  2. 1997 High

    The crystal structure of the RGS4–Giα1 complex revealed that the RGS domain contacts all three Gα switch regions without contributing catalytic residues to the active site, establishing transition-state stabilization as the dominant catalytic mechanism and distinguishing it from Ras GAPs.

    Evidence X-ray crystallography at 2.8 Å resolution of RGS4–Giα1·GDP·AlF4⁻ complex, validated by structure-guided mutagenesis

    PMID:9108480 PMID:9371764 PMID:9430692

    Open questions at the time
    • Whether Asn-128 directly contacts catalytic water remained debated
    • Structure of free RGS4 and induced-fit changes unknown
  3. 1997 High

    Demonstrating that RGS4 also acts as a GAP for Gαq and blocks PLC-β activation—partly by effector-site occlusion—expanded its substrate range beyond Gi to include Gq-mediated signaling pathways.

    Evidence In vitro GTPase and PLC reconstitution assays, cellular MAPK and inositol phosphate assays in COS-7 cells

    PMID:9012799 PMID:9115254 PMID:9177187

    Open questions at the time
    • Relative contribution of GAP versus effector antagonism in intact cells unclear
    • G12/13 family substrates not tested
  4. 1998 High

    The N-terminal amphipathic domain was shown to be essential for plasma membrane targeting, receptor-selective inhibition, and high-potency GAP function, separating the catalytic core from the targeting/selectivity module.

    Evidence N-terminal deletion mutants in reconstituted systems and yeast pheromone assay; GFP localization; palmitoylation site mutagenesis

    PMID:9576926 PMID:9856989

    Open questions at the time
    • Whether palmitoylation is required in mammalian cells remained unresolved
    • Structural basis of receptor selectivity unknown
  5. 1998 High

    RGS4 was shown to inhibit metabotropic glutamate receptor signaling in neurons, providing the first evidence of its physiological role in regulating Gq-coupled neurotransmission.

    Evidence Xenopus oocyte electrophysiology for mGluR1a/5a; patch clamp in hippocampal CA1 neurons

    PMID:9437012

    Open questions at the time
    • Endogenous RGS4 contribution versus other RGS family members not dissected
    • In vivo neuronal role not yet tested
  6. 1999 High

    Cardiac-specific transgenic overexpression demonstrated that RGS4 inhibits pressure-overload-induced ventricular hypertrophy in vivo, establishing its physiological role as a brake on Gq-dependent hypertrophic signaling in the heart.

    Evidence Transgenic mouse model with transverse aortic constriction; hemodynamics and fetal gene expression analysis; GAP-dead N128A mutant as negative control in cardiomyocytes

    PMID:10487771 PMID:9918533

    Open questions at the time
    • Loss-of-function cardiac phenotype not yet examined
    • Specific Gα substrates in cardiomyocytes not identified
  7. 2000 High

    NMR structure of free RGS4 revealed an induced-fit conformational change upon Gα binding, and the N-end rule degradation pathway was identified as the mechanism controlling RGS4 protein turnover, linking its Cys-2 residue to arginylation and proteasomal targeting.

    Evidence Solution NMR spectroscopy; expression-cloning screen in reticulocyte lysate with N-terminal sequencing and mutagenesis

    PMID:10783390 PMID:10852703

    Open questions at the time
    • Identity of the E3 ubiquitin ligase not yet established
    • Whether Cys-2 oxidation is regulated in vivo unknown
  8. 2005 High

    Genetic identification of ATE1, UBR1, and UBR2 as the arginyl-transferase and E3 ligases targeting RGS4 completed the molecular pathway of N-end rule degradation and revealed oxygen/NO-dependent Cys-2 oxidation as a regulatory switch.

    Evidence ATE1−/−, UBR1/UBR2 knockout mouse cells; pulse-chase stability assays; in vivo ubiquitination

    PMID:16217033

    Open questions at the time
    • Physiological oxygen sensing context not fully defined
    • Whether other post-translational modifications cooperate with N-end rule pathway
  9. 2006 High

    RGS4 was found to pre-couple with GPCR–Kir3 channel complexes via direct receptor interaction and to be regulated by PKA/PKG phosphorylation at Ser-52, revealing how scaffolding and kinase signaling tune its GAP activity at the plasma membrane.

    Evidence Co-immunoprecipitation and FRET in live cells; in vitro phosphorylation; S52A mutant; GTPase/PLC assays in smooth muscle cells

    PMID:16885398 PMID:16973624 PMID:17185339

    Open questions at the time
    • Structural basis of GPCR–RGS4 interaction not resolved
    • Whether phosphorylation and palmitoylation are coordinated
  10. 2008 High

    RGS4 knockout mice revealed enhanced parasympathetic bradycardia and impaired IKACh desensitization in sinoatrial node myocytes, establishing RGS4 as a non-redundant regulator of cardiac pacemaking.

    Evidence RGS4−/− mouse; in vivo telemetry; ex vivo perfused heart; SAN myocyte patch clamp

    PMID:18658048

    Open questions at the time
    • Redundancy with other cardiac RGS proteins (RGS6, RGS10) not fully dissected
    • Human cardiac relevance not directly tested
  11. 2010 High

    Beta-cell-specific RGS4 deletion demonstrated that RGS4 tonically suppresses M3 muscarinic receptor/Gq-mediated insulin secretion, identifying it as a physiological regulator of glucose homeostasis.

    Evidence siRNA in MIN6 cells; RGS4-deficient islets; beta-cell-specific knockout mice; calcium imaging and insulin secretion in vivo

    PMID:20385802

    Open questions at the time
    • Whether RGS4 regulates GLP-1R or other incretin receptor pathways in beta cells
    • Compensatory RGS family member expression not assessed
  12. 2012 High

    RGS4 knockout restored endocannabinoid-dependent long-term depression in dopamine-depleted striatum and reduced motor impairment in a Parkinson's model, establishing RGS4 as a link between D2/A2A receptor signaling and synaptic plasticity relevant to basal ganglia function.

    Evidence RGS4−/− mouse; electrophysiological LTD recording; 6-OHDA Parkinson's model; pharmacological pathway dissection

    PMID:22284188

    Open questions at the time
    • Cell-type-specific RGS4 contribution (direct vs indirect pathway MSNs) not isolated
    • Downstream eCB synthesis mechanism not fully defined
  13. 2013 Medium

    Rab GTPase-dependent trafficking of RGS4 between plasma membrane and endosomes was mapped, and NO-induced proteasomal degradation of RGS4 was shown to derepress Gβγ/PI3Kγ/AKT signaling to promote cardiomyocyte hypertrophy, integrating membrane trafficking and degradation as regulatory mechanisms.

    Evidence Dominant-active/negative Rab constructs with live-cell imaging; transgenic PlGF/RGS4/eNOS-KO mouse models; NOS inhibitor studies

    PMID:23454748 PMID:23733193

    Open questions at the time
    • Rab-mediated trafficking studied primarily with overexpressed constructs
    • Whether endosomal RGS4 retains GAP activity unknown
  14. 2015 High

    RGS4 deletion predisposed to atrial fibrillation via enhanced Gαq/11-IP3-mediated Ca²⁺ release, and a selective small-molecule RGS4 inhibitor validated RGS4 as a druggable target in cardiac and neurological disease models.

    Evidence RGS4−/− mouse with atrial burst pacing and Ca²⁺ imaging; CCG-203769 selectivity panel; in vivo bradycardia and akinesia assays

    PMID:25844489 PMID:26088132

    Open questions at the time
    • Long-term in vivo pharmacology and off-target effects of CCG-203769 not characterized
    • Whether RGS4 loss-of-function variants cause human arrhythmia unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of RGS4's direct interaction with GPCRs, the precise mechanism by which Cys-2 oxidation is sensed in vivo, and whether RGS4 functions at endosomes remain unresolved.
  • No high-resolution structure of RGS4 bound to any GPCR
  • Oxygen/NO sensing mechanism for Cys-2 oxidation not reconstituted in defined system
  • Functional significance of endosomal RGS4 pool not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 10 GO:0003924 GTPase activity 5
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 13 R-HSA-112316 Neuronal System 7 R-HSA-392499 Metabolism of proteins 5
Partners
ATE1GNAI1GNAI2GNAO1GNAQKCNJ3PPP1R9AUBR1
Complex memberships
A1R/neurabin/RGS4 complexGPCR-Kir3 channel signaling complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 RGS4 (and GAIP) function as GTPase-activating proteins (GAPs) that accelerate GTP hydrolysis by Gi alpha subunits at least 40-fold; all Gi subfamily members tested were substrates, while Gs alpha was not. In vitro GTPase assay with purified recombinant proteins Cell High 8756726
1996 RGS4 acts catalytically to stimulate GTP hydrolysis by Gi proteins and stabilizes the transition state for GTP hydrolysis, as evidenced by high affinity binding to GDP-AlF4–bound forms of Goa and Gia; it has lower affinity for GTPgammaS- and GDP-bound forms. Purified recombinant protein biochemical assay, AlF4- binding/transition-state analysis The Journal of biological chemistry High 8910288
1997 Crystal structure of RGS4 complexed with Gi alpha1-Mg2+-GDP-AlF4– at 2.8 Å resolution showed the RGS4 core domain binds to the three switch regions of Gi alpha1 without contributing catalytic residues that directly contact GDP or AlF4–, indicating RGS4 catalyzes GTP hydrolysis primarily by stabilizing switch region transition-state conformation; conserved Asn-128 may also interact with the hydrolytic water or Gln-204 side chain. X-ray crystallography at 2.8 Å resolution Cell High 9108480
1997 RGS4 and GAIP act as GAPs for Gq alpha and block activation of phospholipase C beta by GTPgammaS-Gq alpha; the inhibition of PLC beta is not explained solely by GAP activity but also by occlusion of the effector binding site on Galpha. In vitro GTPase assay, plasma membrane reconstitution assay with purified proteins Proceedings of the National Academy of Sciences of the United States of America High 9012799
1997 RGS4 inhibits Gq/11-mediated activation of MAPK and phosphoinositide synthesis in COS-7 cells, acting both as a GAP for Gq/11 (binding Galphaq-GDP-AlF4–) and as an effector antagonist competing with PLC for Galpha binding. Transient transfection and MAPK/inositol phosphate assays in COS-7 cells; AlF4- stimulation in cells overexpressing Galphaq The Journal of biological chemistry High 9115254
1997 Stably expressed RGS4 in mammalian cells attenuated Gi-mediated inhibition of cAMP synthesis and Gq-mediated activation of phospholipase C beta, recapitulating in vitro selectivity in a cellular context. Stable transfection in mammalian cells, cAMP and PLC assays Proceedings of the National Academy of Sciences of the United States of America High 9177187
1997 Mutation of RGS4 residues N88 and L159 (which contact Gi alpha1 in the crystal structure) abolished binding and GAP activity; mutations R167M/A and F168A reduced GAP activity but shifted binding toward the GTPgammaS-bound form, creating RGS antagonists—demonstrating that transition-state stabilization is the predominant mechanism. Mutational analysis combined with GAP assays and in vivo signaling assays (yeast pheromone pathway) Proceedings of the National Academy of Sciences of the United States of America High 9371764
1998 The N-terminal domain of RGS4 (first ~33 aa) confers receptor-selective inhibition of Gq signaling; deletion of this domain eliminates receptor selectivity and reduces potency 10,000-fold; the RGS box alone accelerates GTP hydrolysis while the N-terminus confers high-affinity, receptor-selective inhibition. In vitro reconstitution with N-terminal deletion mutants; receptor-selective inhibition assay The Journal of biological chemistry High 9856989
1998 Plasma membrane localization is required for RGS4 function in vivo; deletion of the N-terminal 33 aa abolishes both plasma membrane localization and signaling inhibition in yeast; adding a C-terminal membrane-targeting sequence to the truncated RGS4 restores both; the N-terminal 33 aa are sufficient to target GFP to the plasma membrane; RGS4 is palmitoylated at Cys-2 and Cys-12, but palmitoylation is not required for membrane localization in yeast. Yeast pheromone response assay, GFP fusion live-cell imaging, palmitoylation site mutagenesis, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 9576926
1998 Multiple RGS4 interface residues contribute additively to GAP activity by stabilizing the transition state conformation; Asn-128 is not exclusively required for catalysis, indicating no single RGS4 residue acts as a classical catalytic 'arginine finger', in contrast to Ras GAPs. Mutational analysis, biochemical binding, and GTPase assays The Journal of biological chemistry High 9430692
1998 RGS4 inhibits signaling by group I metabotropic glutamate receptors (mGluR1a and mGluR5a) in Xenopus oocytes, virtually abolishing calcium-dependent chloride currents; it also markedly attenuates mGluR5-mediated inhibition of potassium currents in hippocampal CA1 neurons, at concentrations matching those for PLC inhibition. Xenopus oocyte electrophysiology, hippocampal neuron patch clamp, reconstituted PLC assay The Journal of neuroscience : the official journal of the Society for Neuroscience High 9437012
1998 Expression of GTPase-deficient Gi alpha2-Q204L causes translocation of cytoplasmic RGS4 to the plasma membrane, suggesting RGS4 can be recruited to the membrane indirectly by G-protein activation; in the absence of this stimulus, the majority of cellular RGS4 is cytoplasmic. Subcellular fractionation, co-expression of GTPase-deficient G protein mutant, immunofluorescence The Journal of biological chemistry Medium 9660808
1999 RGS4 is palmitoylated at a conserved Cys-95 within the RGS domain (autopalmitoylation with palmitoyl-CoA); palmitoylation of Cys-95 inhibits GAP activity 80–100% in solution-based assays but potentiates GAP activity in receptor-G protein proteoliposomes; dual palmitoylation at Cys-2/12 and Cys-95 is inhibitory. Metabolic [3H]palmitate labeling in Sf9 cells, autopalmitoylation assay, single-turnover and steady-state GTPase assays, site-directed mutagenesis The Journal of biological chemistry High 10608901
1999 The N-terminal amphipathic helix (residues 12–30) of RGS16 is sufficient for membrane association, and equivalent structural features are conserved in RGS4 and RGS5; hydrophobic residues of the nonpolar face and positively charged residues along the polar/nonpolar interface are required; RGS4/16 are peripheral membrane proteins and membrane association does not require palmitoylation. Subcellular fractionation, differential centrifugation, site-directed mutagenesis, GFP fusion localization The Journal of biological chemistry Medium 10391923
1999 Transgenic cardiac-specific overexpression of RGS4 markedly reduced ventricular hypertrophy and cardiac fetal gene program induction in response to pressure overload (transverse aortic constriction), establishing RGS4 as a GAP that inhibits the G protein-dependent hypertrophic signaling pathway in vivo. Transgenic mouse model, hemodynamic measurements, gene expression analysis The Journal of clinical investigation High 10487771
1999 RGS4 inhibits G-protein signaling in cardiomyocytes; Gq-coupled receptor agonist (phenylephrine, endothelin-1)-mediated gene induction and cardiomyocyte hypertrophy are blocked by RGS4 but not by the N128A-RGS4 GAP-dead mutant, demonstrating that GAP activity is required. Cardiomyocyte transfection, reporter gene assay, point mutant (N128A) functional analysis Circulation High 9918533
2000 NMR solution structure of free RGS4 reveals a backbone rmsd of 1.94 Å compared with the Galpha-bound crystal structure, demonstrating that RGS4 undergoes an induced conformational change upon binding Gi alpha1, involving a kink in the helix at residues K116–Y119 that reorganizes the binding pocket. 2D/3D heteronuclear NMR spectroscopy, 2871 restraints, comparison with existing X-ray structure Biochemistry High 10852703
2000 RGS4 is arginylated and degraded by the N-end rule pathway in reticulocyte lysate; the degron resides at the N-terminus; Cys-2 must become N-terminal (following Met removal) and is then arginylated, with N-terminal Arg acting as a destabilizing residue recognized by the ubiquitin/proteasome system. Expression-cloning screen in reticulocyte lysate, radiochemical N-terminal sequencing, site-directed mutagenesis of N-terminal residues The Journal of biological chemistry High 10783390
2000 RGS4 selectively enhances alpha2A-adrenoreceptor-stimulated GTPase activity of Galpha(o1) and Galpha(i2) but not Galpha(i1) or Galpha(i3), increasing both Vmax and Km for GTP in an enzyme kinetic analysis, demonstrating G protein subtype-selective GAP action in the context of receptor activation. Receptor-Galpha fusion protein GTPase assay in COS-7 cells, enzyme kinetic analysis The Journal of biological chemistry Medium 10807934
2001 RGS4 is required for the agonist concentration-dependent relaxation (voltage-dependent kinetics) of G protein-gated inwardly rectifying K+ (KG/Kir3) channels in Xenopus oocytes; this effect requires the RGS domain and its interaction with pertussis toxin-sensitive Galpha subunits, not Gs-coupled pathways. Xenopus oocyte electrophysiology, truncation and point mutants of RGS4, selective G protein coupling experiments The Journal of physiology High 11507164
2001 Dual-transgenic overexpression of RGS4 in Galphaq-40 transgenic hearts normalized fractional shortening, LV dimensions, PKC xi membrane translocation, and fetal gene expression, establishing RGS4 as a Galphaq GAP in the in vivo heart. Dual transgenic mouse model, echocardiography, Western blot for PKC translocation, gene expression Journal of molecular and cellular cardiology High 11162127
2002 Recombinant RGS4 blunted endothelin-1-stimulated PLC activity in human LV membranes; adenoviral RGS4 overexpression in rabbit ventricular myocytes abolished the inotropic effect of ET-1, implicating upregulated RGS4 in desensitization of Gq/11-mediated signaling in failing myocardium. Recombinant protein addition to human cardiac membranes (PLC assay), adenoviral gene transfer in isolated cardiomyocytes Cardiovascular research Medium 12176127
2003 GFP-RGS4 expressed in HEK293 cells localizes to the cytosol but is selectively recruited to the plasma membrane by coexpression with Galpha(i2) or M2 muscarinic receptor; G protein mutants with reduced RGS affinity do not produce this effect, demonstrating that recruitment involves direct G protein binding and is independent of downstream signaling. GFP live-cell imaging, subcellular localization, G protein mutant coexpression, steady-state Gi GTPase assay Molecular pharmacology Medium 12920194
2003 Endogenous RGS4 in rat brain and PC12 cells localizes predominantly to membrane fractions (not cytosolic as seen with transfected tagged protein); endogenous RGS4 is a single 27–28 kDa protein and its expression level is strongly controlled by proteolysis. Subcellular fractionation, Western blot with specific antibodies detecting endogenous protein The Journal of biological chemistry Medium 14604980
2005 ATE1 Arg-transferase mediates in vivo degradation of RGS4 and RGS5 via the N-end rule pathway; sequential modifications (N-terminal exposure of Cys-2, its oxidation, then arginylation) act as a licensing mechanism before ubiquitin ligases UBR1/UBR2 target RGS4 for proteasomal degradation; hypoxia perturbs this proteolysis; Cys-2 mutants are long-lived in vivo. ATE1-/- and UBR1/UBR2 knockout mouse cells, pulse-chase protein stability, site-directed mutagenesis, in vivo ubiquitination assays Proceedings of the National Academy of Sciences of the United States of America High 16217033
2006 GABA(B) receptors, Kir3 channels, Galpha(o), and RGS4 are in close proximity (<100 Å) at the plasma membrane of living HEK293 cells, as demonstrated by FRET between CFP/YFP-tagged proteins; significant FRET (~13%) occurs between RGS4 and GABA(B) R1 or R2 subunits, indicating physical association in a signaling complex. FRET combined with total internal reflection fluorescence microscopy in live HEK293 cells The Journal of physiology Medium 17185339
2006 RGS4 associates with GPCR-Kir3 channel complexes via both its N-terminal domain and RGS domain; unlike RGS3s which acts by 'collision coupling', RGS4 'precouples' to the GPCR-Kir3 complex (with the GPCR as the major RGS4 interaction target), resulting in ~100-fold greater potency in accelerating G protein-dependent Kir3 channel-gating kinetics without attenuation of current amplitude. Co-immunoprecipitation from CHO-K1 cells, deletion and chimeric RGS constructs, electrophysiology (Kir3 channel gating kinetics) The Journal of biological chemistry High 16973624
2006 PKA and PKG phosphorylate RGS4 at Ser-52, causing its translocation from cytosol to plasma membrane, enhanced association with Galpha(q)-GTP, and increased intrinsic Galpha(q) GTPase activity; expression of RGS4(S52A) blocks PKA/PKG-induced increases in GTPase activity and inhibition of PI hydrolysis, demonstrating phosphorylation of RGS4 as a mechanism by which PKA/PKG inhibit Gq-mediated PLC-beta1 activity. In vitro phosphorylation, subcellular fractionation, co-immunoprecipitation, phosphorylation-dead mutant (S52A), PLC/GTPase assays in gastric smooth muscle cells American journal of physiology. Cell physiology High 16885398
2006 The small molecule CCG-4986 inhibits RGS4 by covalently modifying Cys-132 on the Galpha-interaction face of the RGS domain; mutation of Cys-132 abolishes CCG-4986 sensitivity; the mechanism was confirmed by mass spectrometry identifying a 153-Da fragment covalently attached to surface-exposed cysteines. Surface plasmon resonance, FRET assay, single-turnover GTPase assay, site-directed mutagenesis, mass spectrometry Biochimica et biophysica acta High 17660054
2007 N-terminal residues of RGS4 control proteasomal degradation in HEK293 cells; stabilizing mutation C2S enhances RGS4 expression and function; the N-end rule degradation pathway strongly controls cellular RGS4 levels and, consequently, its GAP function. N-terminal mutagenesis, protein stability assays, GPCR signaling functional assays in HEK293 cells Molecular pharmacology Medium 17220356
2007 IL-1beta upregulates RGS4 expression in colonic smooth muscle via the canonical IKK2/IkappaBalpha/NF-kappaB pathway; siRNA knockdown of RGS4 blocked IL-1beta's inhibitory effect on acetylcholine-stimulated PLC-beta activation and initial contraction, confirming RGS4 as the mediator of IL-1beta-induced inhibition of smooth muscle contraction. siRNA knockdown, IKK2 inhibitors, NF-kappaB reporter assay, PLC-beta assay, smooth muscle contraction assay The Biochemical journal Medium 18260825
2008 RGS4-null mice show enhanced bradycardic responses to parasympathetic agonists and decreased GIRK channel desensitization (IKACh) in sinoatrial node myocytes, establishing RGS4 as a regulator of parasympathetic tone in the sinoatrial node by inhibiting Gi/o signaling and IKACh kinetics. RGS4-null mouse model, in vivo heart rate telemetry, ex vivo perfused heart, SAN myocyte patch clamp electrophysiology Circulation research High 18658048
2009 RGS4 directly interacts with the delta-opioid receptor (via C-tail and third intracellular domain) but not with the mu-opioid receptor, as shown by co-immunoprecipitation; endogenous RGS4 knockdown specifically increases delta-opioid receptor agonist (SNC80) potency and MAPK activation, with no change in mu-opioid (morphine) responses. Stable shRNA knockdown of endogenous RGS4, co-immunoprecipitation with receptor chimeras, cAMP and MAPK assays The Journal of biological chemistry High 19416973
2010 RGS4 is a potent negative regulator of M3 muscarinic receptor (M3R)/Gq-mediated augmentation of glucose-stimulated insulin secretion in pancreatic beta-cells; siRNA knockdown of RGS4 in MIN6 cells and deletion in mouse islets greatly enhances M3R-mediated calcium release and insulin secretion; beta-cell-specific RGS4 deletion in vivo increases plasma insulin and reduces blood glucose after muscarinic agonist treatment. siRNA knockdown in MIN6 cells, RGS4-deficient mouse islets, beta-cell-specific knockout mice, calcium imaging, insulin secretion assay, in vivo glucose/insulin measurements Proceedings of the National Academy of Sciences of the United States of America High 20385802
2011 Opioid agonist (DAMGO, DPDPE) treatment causes proteasomal and lysosomal degradation of RGS4 protein in SH-SY5Y cells via a ubiquitin-dependent mechanism; polyubiquitinated RGS4 accumulates with proteasome inhibitors; MOR agonist-induced RGS4 degradation is blocked by pertussis toxin, indicating Gi/o dependence; downstream effect is cross-talk between delta-OR and M3 muscarinic receptor signaling through RGS4. Proteasome inhibitors (MG132, lactacystin), pertussis toxin, Western blot, ubiquitination assay, functional signaling assays The Journal of biological chemistry Medium 21209077
2012 RGS4 is a key link between D2/A2A receptor cAMP/PKA signaling and endocannabinoid (eCB) mobilization in striatal indirect-pathway MSNs; RGS4-/- mice show normal eCB-LTD after dopamine depletion and significantly less motor impairment in the 6-OHDA Parkinson's model, establishing RGS4 as mediating dopaminergic regulation of eCB-LTD. RGS4 knockout mouse, electrophysiology (LTD recording), 6-OHDA mouse model, pharmacological dissection of signaling pathways Neuron High 22284188
2012 Neurabin scaffolds RGS4 with the adenosine A1 receptor (A1R) to form a complex that attenuates A1R signaling; loss of neurabin enhances A1R signaling and anti-seizure protection; RGS4 inhibitor administered in vivo attenuates seizure severity, demonstrating the A1R/neurabin/RGS4 complex as a functional regulatory unit. Co-immunoprecipitation (complex assembly), neurabin knockout mouse, RGS4 inhibitor in vivo, kainate seizure model The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 22357852
2013 NO production from endothelial cells induces proteasomal degradation of RGS4, thereby relieving repression of the Gbeta-gamma/PI3K-gamma/AKT/mTORC1 pathway and stimulating cardiomyocyte growth; NOS inhibitor L-NAME attenuates RGS4 degradation; eNOS knockout mice do not develop myocardial hypertrophy upon PlGF overexpression; transgenic RGS4 expression prevents hypertrophy. Transgenic mouse models (PlGF, RGS4, eNOS KO), NOS inhibitor, proteasomal degradation assay, AKT/mTORC1 signaling analysis The Journal of clinical investigation High 23454748
2013 Rab5 activation decreases RGS4 plasma membrane levels and increases its endosomal targeting; Rab7 promotes TGN association of RGS4; Rab11 mediates RGS4 recycling to the plasma membrane (Cys-12 is required for Rab11-mediated trafficking); inhibition of Rab11 decreases RGS4 function as inhibitor of M1R activity without affecting M1R/Gq localization or function. Rab GTPase dominant-active/dominant-negative constructs, live-cell imaging, co-localization with endosomal markers, functional M1R signaling assay The Journal of biological chemistry Medium 23733193
2014 RGS4 forms distinct G protein-dependent complexes with PAR1: RGS4 interaction with PAR1 requires Galpha(o) (not other Galpha), demonstrated by BRET; purified PAR1 intracellular third loop directly binds purified RGS4; RGS4 selectively inhibits PAR1/Gao-mediated MAPK/ERK signaling but not RhoA signaling. BRET in live COS-7 cells, pulldown with purified GST-fusion proteins, functional MAPK/ERK and RhoA signaling assays PloS one Medium 24743392
2015 RGS4 deletion results in predisposition to atrial fibrillation; RGS4-/- atrial cells show increased Ca2+ spark frequency and abnormal spontaneous Ca2+ release; the mechanism involves enhanced Galpha(q/11)-IP3 pathway activity leading to abnormal Ca2+ release and abnormal electrical events. RGS4-/- mouse model, in vivo atrial burst pacing, isolated atrial cell Ca2+ imaging, multielectrode array The Journal of biological chemistry High 26088132
2015 The thiadiazolidinone inhibitor CCG-203769 selectively inhibits RGS4 (8- to >5000-fold selectivity over other RGS proteins, 300-fold over GSK-3beta); it enhances Galphaq-dependent Ca2+ signaling in an RGS4-dependent manner, enhances Galphai-dependent delta-OR inhibition of cAMP, potentiates muscarinic bradycardia in vivo, and reverses raclopride-induced akinesia in mice (Parkinson's model). Biochemical selectivity panel, Ca2+ signaling assay in RGS4-expressing cells, in vivo bradycardia and akinesia assays, cAMP assay in SH-SY5Y cells ACS chemical neuroscience High 25844489

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 702 9108480
1996 GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Cell 676 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 294 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 229 16217033
1998 The N-terminal domain of RGS4 confers receptor-selective inhibition of G protein signaling. The Journal of biological chemistry 212 9856989
1999 RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. The Journal of clinical investigation 167 10487771
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
2006 Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Human genetics 114 17006672
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
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 Confirming RGS4 as a susceptibility gene for schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 101 14755443
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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 The membrane association domain of RGS16 contains unique amphipathic features that are conserved in RGS4 and RGS5. The Journal of biological chemistry 89 10391923
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
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
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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
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2002 Abused drugs modulate RGS4 mRNA levels in rat brain: comparison between acute drug treatment and a drug challenge after chronic treatment. Neurobiology of disease 75 12270694
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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
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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
2007 Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. Journal of psychiatric research 67 17408693
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
2004 Regulators of G-protein signaling 3 and 4 (RGS3, RGS4) are associated with glioma cell motility. Journal of neuropathology and experimental neurology 61 15055445
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
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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
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
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 54 15548600
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
1997 Inhibition of regulator of G protein signaling function by two mutant RGS4 proteins. Proceedings of the National Academy of Sciences of the United States of America 50 9371764
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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
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
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2002 Characterization and comparison of RGS2 and RGS4 as GTPase-activating proteins for m2 muscarinic receptor-stimulated G(i). Molecular pharmacology 39 12181442
2011 Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse. Molecular and cellular neurosciences 38 21215802
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
2012 Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment. Oncogene 37 22562250
1997 Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization. Biochemical and biophysical research communications 37 9425263
2020 Targeting RGS4 Ablates Glioblastoma Proliferation. International journal of molecular sciences 36 32392739
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
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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
2007 Linkage disequilibrium patterns and functional analysis of RGS4 polymorphisms in relation to schizophrenia. Schizophrenia bulletin 32 17515439
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
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
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
2022 Bisphenol-A impairs synaptic formation and function by RGS4-mediated regulation of BDNF signaling in the cerebral cortex. Disease models & mechanisms 28 35781563
2011 RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling. Psychopharmacology 28 22193724
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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
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