Affinage

RGS5

Regulator of G-protein signaling 5 · UniProt O15539

Length
181 aa
Mass
20.9 kDa
Annotated
2026-04-28
77 papers in source corpus 30 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS5 is a GTPase-activating protein (GAP) for Gαi and Gαq subunits that functions as a critical modulator of G-protein-coupled receptor signaling in vascular smooth muscle cells, pericytes, and other cell types to regulate vascular tone, remodeling, and tissue homeostasis. RGS5 accelerates GTP hydrolysis on Gαi1/2/3, Gαo, and Gαq, thereby attenuating signaling downstream of angiotensin II/AT1R, endothelin-1, sphingosine-1-phosphate, PDGF, and calcium-sensing receptors, and it suppresses hedgehog signaling by inhibiting Gαi downstream of Smoothened (PMID:11253162, PMID:12006602, PMID:12514120, PMID:23637832, PMID:30690792). Its stability is controlled by the N-end rule pathway, in which N-terminal Cys-2 oxidation triggers ATE1-mediated arginylation and UBR1/UBR2-dependent proteasomal degradation — a process modulated by hypoxia — while PKC phosphorylation at Ser166 inactivates GAP function, and its N-terminal amphipathic helix is required for membrane targeting (PMID:16217033, PMID:17220356, PMID:17540411, PMID:11253162). In vivo, Rgs5 loss causes hypotension, prolonged cardiac repolarization, abnormal tumor vasculature, age-dependent myocardial fibrosis through pericyte-derived TGFβ2 secretion, and in astrocytes RGS5 binds TNFR1/TNFR2 to amplify TNF-driven neuroinflammation; in the tumor microenvironment, TGFβ-induced pSmad2 binds RGS5 and sequesters it to the nucleus, switching pericytes from pro-apoptotic to pro-survival signaling (PMID:18268011, PMID:18418378, PMID:23079193, PMID:38563133, PMID:37674228, PMID:34012071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1999 Medium

    Establishing the structural basis for membrane targeting: mutagenesis of RGS16 defined an N-terminal amphipathic helix whose hydrophobic face and charged residues are required for peripheral membrane association, a feature conserved in RGS5.

    Evidence Site-directed mutagenesis and subcellular fractionation of RGS16, with conservation analysis to RGS4/RGS5

    PMID:10391923

    Open questions at the time
    • The amphipathic helix was characterized in RGS16, not RGS5 directly
    • Lipid-binding specificity of the helix is unknown
  2. 2001 High

    Defining RGS5 as a selective GAP for Gαi and Gαq established its core biochemical activity and showed it suppresses Gq-coupled GPCR (AT1R, ET-1) calcium signaling, answering which G-protein subtypes it acts on.

    Evidence In vitro GAP assay with recombinant proteins; calcium transient assays in AT1a-expressing 293T cells; subcellular fractionation showing N-terminal 33 residues required for membrane targeting

    PMID:11253162

    Open questions at the time
    • No structural detail of Gα–RGS5 interface at this point
    • Endogenous relevance in native cells not yet shown
  3. 2002 High

    Loss-of-function in native vascular smooth muscle cells demonstrated that endogenous RGS5 selectively restrains AT1R-Gq/11 signaling (MAPK, inositol phosphate) but not other GPCRs, establishing receptor selectivity in a physiological context.

    Evidence Ribozyme-mediated RGS5 knockdown in rat aortic smooth muscle cells with MAPK and IP release readouts

    PMID:12006602

    Open questions at the time
    • Mechanism of receptor selectivity (direct AT1R interaction vs. subcellular compartmentalization) unresolved
  4. 2003 High

    Broadening the ligand repertoire showed RGS5 attenuates signaling from multiple GPCR agonists (AngII, ET-1, S1P, PDGF) relevant to pericyte biology, positioning it as a multi-receptor signaling brake in the vasculature.

    Evidence ERK-2 phosphorylation assays across multiple ligands in pericyte-relevant cellular contexts

    PMID:12514120

    Open questions at the time
    • Pericyte-specific phenotypic consequences not yet tested in vivo
  5. 2005 High

    The discovery that RGS5 is degraded via the N-end rule pathway — requiring Cys-2 oxidation, ATE1-mediated arginylation, and UBR1/UBR2 ubiquitin ligases — and that hypoxia perturbs this degradation, revealed an oxygen-sensing mechanism controlling RGS5 protein levels.

    Evidence ATE1-KO and UBR1/UBR2-KO mice, Cys-2 mutant stability assays, hypoxia experiments

    PMID:16217033

    Open questions at the time
    • Identity of the oxidase acting on Cys-2 remains unknown
    • In vivo vascular consequences of hypoxia-stabilized RGS5 not directly tested
  6. 2005 Medium

    A short splice variant (RGS5s) lacking 108 N-terminal residues is cytosolic and GAP-inactive, and acts as a dominant-negative competitor, revealing a potential endogenous regulatory mechanism.

    Evidence RT-PCR cloning, fractionation, calcium assays, and co-transfection competition in HEK293 cells

    PMID:15670159

    Open questions at the time
    • Physiological expression levels and tissue distribution of RGS5s unclear
    • In vivo relevance of dominant-negative function not established
  7. 2007 High

    Identification of PKC-mediated phosphorylation at Ser166 as a switch that abolishes Gα binding and GAP activity provided a feedback mechanism by which Gαq→PKC signaling can inactivate its own negative regulator.

    Evidence In vitro PKC assay, mass spectrometry of Ser166, S166D phosphomimetic mutagenesis with Ca2+ and Gα-binding readouts

    PMID:17540411

    Open questions at the time
    • Which PKC isoform(s) are responsible in vivo is not defined
    • Whether Ser166 phosphorylation is reversible by specific phosphatases is unknown
  8. 2008 High

    Rgs5-knockout mice revealed two major in vivo roles: systemic hypotension with exaggerated vasodilatory signaling in aortic SMCs, and pericyte-driven tumor vascular normalization upon RGS5 loss, establishing RGS5 as a regulator of both arterial tone and tumor vasculature.

    Evidence Rgs5-KO mice with blood pressure measurement, aortic SMC phosphorylation assays; tumor transplant models with vascular permeability, immune infiltration, and histology

    PMID:18268011 PMID:18418378

    Open questions at the time
    • Downstream effectors mediating tumor vascular normalization not fully delineated
    • Whether RGS5 loss affects immune evasion independently of vascular normalization is unclear
  9. 2009 High

    RGS5 was identified as a HIF-1-dependent hypoxia-responsive gene that induces caspase-3-mediated apoptosis and antagonizes VEGF signaling via p38 activation, linking its expression to oxygen-sensing transcriptional programs.

    Evidence HIF-1β-KO endothelial cells, RGS5 overexpression and siRNA knockdown, Annexin V and caspase-3 assays, p38 inhibitor studies

    PMID:19564336

    Open questions at the time
    • Whether HIF-1-dependent transcription and N-end rule protein stabilization operate synergistically or redundantly under hypoxia
  10. 2012 High

    Two new physiological roles were defined: RGS5 controls cardiac repolarization via regulation of voltage-dependent K+ channels (Kv4.2/4.3, Kv1.5, Kv2.1), and in VSMCs it is a PPARγ/δ transcriptional target that preserves BKCa channel activity to control myogenic tone by suppressing PKC.

    Evidence Rgs5-KO mouse electrophysiology (QT prolongation, patch clamp, Kv channel expression); PPARγ response element binding, siRNA, patch clamp, myogenic tone in transgenic mice

    PMID:22962432 PMID:23079193

    Open questions at the time
    • Mechanism linking RGS5 loss to Kv channel downregulation is indirect — whether transcriptional or post-translational is unknown
    • Whether PPARγ regulation of RGS5 is relevant outside the mesenteric vasculature
  11. 2013 High

    RGS5 was shown to repress hedgehog signaling by co-immunoprecipitating with Smoothened and co-localizing in primary cilia, with overexpression inhibiting and knockdown potentiating Shh-mediated osteogenesis, extending its function beyond classical Gαi/q signaling.

    Evidence Co-IP, immunohistochemistry in primary cilia, OE and siRNA in C3H10T1/2 cells with osteogenesis readout

    PMID:23637832

    Open questions at the time
    • Whether RGS5 acts on Gαi downstream of Smo or through a direct Smo interaction is unresolved
    • In vivo hedgehog-related phenotype in Rgs5-KO mice not reported
  12. 2014 High

    A signaling switch model was established: RGS5 preferentially inhibits Gαq/11→PKC, thereby enabling Gα12/13→RhoA signaling in VSMCs — explaining how RGS5 promotes arteriogenesis by balancing competing G-protein pathways rather than uniformly suppressing all signaling.

    Evidence OE/KD/KO approaches with RhoA activation, calcium mobilization, and collateral arteriole growth measurements

    PMID:24972930

    Open questions at the time
    • How RGS5 achieves selectivity for Gαq/11 over Gα12/13 at the structural level is unknown
  13. 2017 High

    Proximity ligation demonstrated that RGS5 physically associates with AT1R upon activation in VSMCs, and this translocation is impaired in spontaneously hypertensive rats, providing a mechanism for receptor-proximal GAP activity and its failure in hypertension.

    Evidence In situ PLA in primary VSMCs, siRNA knockdown with myogenic response measurement, comparison of normotensive vs. SHR arterioles

    PMID:29061726

    Open questions at the time
    • Whether impaired RGS5 translocation in SHR is cause or consequence of hypertension
    • Direct binding interface between RGS5 and AT1R not mapped
  14. 2018 High

    Mechanical stretch/hypertensive pressure was shown to upregulate RGS5 in VSMCs, which then enables RhoA-mediated stress fiber formation through Gαq/11 suppression, establishing RGS5 as a mechanosensitive effector of vascular remodeling.

    Evidence Rgs5-KO mice under hypertension, mechanical stretch of VSMCs, RhoA assay, PKC inhibitor phenocopy

    PMID:29208700

    Open questions at the time
    • Transcriptional mechanism by which stretch induces RGS5 expression is not defined
  15. 2019 High

    RGS5 inhibits calcium-sensing receptor signaling in parathyroid cells: transgenic overexpression causes hyperparathyroidism and parathyroid neoplasia while Rgs5-null mice have low PTH, revealing an endocrine role beyond the vasculature.

    Evidence Parathyroid-targeted RGS5 transgenic and Rgs5-null mice, CASR signaling in human parathyroid cells

    PMID:30690792

    Open questions at the time
    • Whether RGS5 acts on Gαi or Gαq downstream of CASR is not dissected
    • Relevance to human parathyroid disease not established
  16. 2021 High

    TGFβ-induced pSmad2 was found to bind RGS5 and sequester it to the nucleus in tumor pericytes, switching RGS5 from a pro-apoptotic to pro-survival factor by rescuing PI3K-AKT signaling, revealing how the tumor microenvironment co-opts RGS5.

    Evidence Co-IP of pSmad2–RGS5, nuclear fractionation, PI3K-AKT and apoptosis assays in tumor pericytes

    PMID:34012071

    Open questions at the time
    • Whether nuclear RGS5 has transcriptional or other nuclear functions beyond Smad2 sequestration
    • Generalizability across tumor types not tested
  17. 2021 High

    RGS5 overexpression in proliferating VSMCs was shown to promote quiescence primarily through Gαi/o suppression (attenuating ERK1/2 and Akt), pharmacologically dissecting which Gα subtype mediates the growth-arrest phenotype.

    Evidence OE with selective Gαi/o vs. Gαq/11 inhibitors, ERK/Akt phosphorylation, proliferation and migration assays

    PMID:34359918

    Open questions at the time
    • Identity of the Gαi-coupled receptor driving VSMC proliferation that RGS5 opposes is not specified
  18. 2023 High

    A non-canonical, G-protein-independent function was identified: RGS5 directly binds TNFR1 and TNFR2 in astrocytes to amplify TNF-driven neuroinflammation, and astrocyte-specific Rgs5 deletion mitigates neuroinflammation in Parkinson's disease models.

    Evidence Astrocyte-specific conditional Rgs5-KO, Co-IP of RGS5 with TNFR1/TNFR2, cytokine assays, PD animal models

    PMID:37674228

    Open questions at the time
    • Mechanism by which RGS5 binding to TNFRs amplifies signaling (scaffolding, receptor stabilization?) is undefined
    • Whether this is Gα-dependent or entirely independent is unresolved
  19. 2024 High

    Age-dependent loss of RGS5 in cardiac pericytes was shown to drive myocardial fibrosis through secretion of TGFβ2 and PDGFB, which activate fibroblasts in a paracrine manner, establishing RGS5 as a guardian against cardiac aging.

    Evidence In vivo Rgs5 deletion, pericyte-fibroblast co-culture, TGFβ2 neutralization rescue, snRNA-seq, histology

    PMID:38563133

    Open questions at the time
    • What triggers age-dependent RGS5 downregulation in pericytes is unknown
    • Whether restoring RGS5 can reverse established fibrosis is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of RGS5 selectivity for Gαq/11 over Gα12/13, the identity of the Cys-2 oxidase, whether nuclear RGS5–pSmad2 complexes have transcriptional roles, and the mechanism by which RGS5 binding to TNFRs amplifies rather than dampens signaling.
  • No high-resolution structure of full-length RGS5 or its TNFR complexes
  • Cys-2 oxidase identity unknown
  • Nuclear function of RGS5 beyond Smad sequestration uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0003924 GTPase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
ATE1GNAI3GNAQSMAD2SMOTNFRSF1AUBR1UBR2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 RGS5 binds to Gαi1, Gαi2, Gαi3, Gαo, and Gαq (but not Gαs or Gα13) in the presence of GDP/AlF4-, and accelerates the GTPase activity of Gαi3, functioning as a GTPase-activating protein (GAP) for these G-protein subunits. In vitro binding assay with GDP/AlF4-, GTPase activity assay with recombinant proteins Life sciences High 11253162
2001 RGS5 suppresses angiotensin II- and endothelin-1-induced intracellular Ca2+ transients when expressed in AT1a receptor-expressing 293T cells, confirming its role as a negative regulator of Gq-coupled GPCR signaling. Calcium transient assay in transfected 293T cells overexpressing RGS5 Life sciences High 11253162
2001 The N-terminal region (amino acids 1–33) of RGS5 is required for membrane targeting; deletion of this region causes RGS5 to localize exclusively to the cytosolic fraction, though GAP activity is retained. Subcellular fractionation of cells expressing full-length vs. ΔN-RGS5 Life sciences Medium 11253162
1999 The N-terminal amphipathic alpha-helix of RGS16 (amino acids 12–30), whose hydrophobic face and positively charged residues are required for membrane association, defines structural features conserved in RGS4 and RGS5, indicating a shared peripheral membrane-targeting mechanism. Site-directed mutagenesis, subcellular fractionation, differential centrifugation The Journal of biological chemistry Medium 10391923
2002 Endogenous RGS5 selectively inhibits angiotensin II AT1a receptor-mediated MAP kinase activation and inositol phosphate release through Gq/11 signaling in rat vascular smooth muscle cells, as demonstrated by ribozyme-mediated knockdown. Synthetic ribozyme knockdown, MAP kinase activation assay, inositol phosphate release assay in rat aortic smooth muscle cells The Journal of biological chemistry High 12006602
2003 RGS5 acts as a potent GAP for Gαi and Gαq and attenuates angiotensin II-, endothelin-1-, sphingosine-1-phosphate-, and PDGF-induced ERK-2 phosphorylation in pericyte cellular contexts. ERK-2 phosphorylation assay in cells expressing RGS5; correlation with pericyte-specific expression pattern FASEB journal High 12514120
2005 RGS4 and RGS5 are in vivo substrates of the N-end rule ubiquitin-proteasome pathway: the ATE1 arginyltransferase arginylates oxidized N-terminal Cys-2 of RGS5, targeting it for degradation via ubiquitin ligases UBR1 and UBR2; mutant RGS5 with Cys-2 blocked from becoming N-terminal is long-lived. Genetic (ATE1 knockout, UBR1/UBR2 knockout mice), mutant RGS5 stability assay in vivo and in cells Proceedings of the National Academy of Sciences High 16217033
2005 Hypoxia perturbs the proteolysis of RGS5 via the N-end rule pathway, implicating an O2-ATE1-UBR1/UBR2 circuit as a mechanism coupling oxygen levels to RGS5 stability and G protein signaling. Cell-based protein stability assay under hypoxic conditions with ATE1 and UBR1/UBR2 knockouts Proceedings of the National Academy of Sciences High 16217033
2007 N-terminal residues of RGS5 (specifically Cys-2 and the N-end rule determinant) control proteasomal degradation; stabilizing mutation C2S enhances RGS5 expression and function in HEK293 cells. Site-directed mutagenesis (C2S), protein expression quantification, functional assay in HEK293 cells Molecular pharmacology High 17220356
2007 Protein kinase C phosphorylates RGS5 at Ser166, abolishing its binding to Gα subunits and its GAP activity; substitution of Ser166 with aspartic acid mimics phosphorylation and markedly reduces inhibition of ET-1-induced Ca2+ responses. In vitro PKC phosphorylation assay, mass spectrometry, site-directed mutagenesis (S166D), Ca2+ assay, Gα binding assay Life sciences High 17540411
2008 Loss of Rgs5 in mice results in persistently low blood pressure and dilated aortas; isolated aortic smooth muscle cells from Rgs5-/- mice show exaggerated phosphorylation of VASP and ERK in response to sodium nitroprusside or sphingosine-1-phosphate, indicating RGS5 attenuates vasodilatory signaling. Rgs5 knockout mouse, blood pressure measurement, aortic smooth muscle cell isolation, phosphorylation assays Molecular and cellular biology High 18268011
2008 Loss of Rgs5 in tumors leads to pericyte maturation and vascular normalization, reducing tumor hypoxia and vessel leakiness, and increasing immune effector cell infiltration, establishing RGS5 as a master regulator of abnormal tumor vascular morphology through G-protein signaling. Rgs5 knockout mouse tumor model, histology, vascular permeability assay, immune cell infiltration analysis Nature High 18418378
2009 RGS5 is a HIF-1-dependent hypoxia-inducible gene in endothelial cells; overexpression of RGS5 induces apoptosis via caspase-3 activation and increased Bax/Bcl-2 ratio, and antagonizes VEGF angiogenic signaling by activating p38 (but not ERK1/2). HIF-1β knockout cells, RGS5 overexpression, siRNA knockdown, Annexin V assay, caspase-3 activation assay, p38 inhibitor, Matrigel assay The Journal of biological chemistry High 19564336
2011 Beta-agonist exposure of airway smooth muscle cells reduces RGS5 expression, leading to augmented procontractile signaling; RGS5 knockdown increases agonist-evoked intracellular Ca2+ flux and myosin light chain phosphorylation, and Rgs5-/- mouse lung slices contract more to carbachol. siRNA knockdown, Ca2+ flux assay, MLC phosphorylation assay, Rgs5 KO mouse lung slice contraction assay The Journal of biological chemistry High 21278382
2012 RGS5 is a transcriptional target of PPARγ and PPARδ in vascular smooth muscle cells; RGS5 blunts angiotensin II-mediated protein kinase C activation and preserves large conductance Ca2+-activated K+ (BKCa) channel activity, thereby controlling myogenic tone in mesenteric arteries. Gene expression profiling, PPAR response element binding assay, siRNA targeting RGS5, patch clamp, myogenic tone measurement in transgenic mice with dominant-negative PPARγ Circulation research High 22962432
2013 RGS5 acts as an endogenous repressor of hedgehog signaling: RGS5 overexpression inhibits Shh-mediated signaling and osteogenesis in C3H10T1/2 cells, while siRNA-mediated knockdown potentiates Shh signaling; RGS5 co-immunoprecipitates with Smoothened (Smo) and co-localizes with Smo in primary cilia. Overexpression, siRNA knockdown, co-immunoprecipitation, immunohistochemical analysis of primary cilia, osteogenesis assay PloS one High 23637832
2014 RGS5 promotes arteriogenesis by inhibiting Gαq/11-mediated calcium mobilization in vascular smooth muscle cells, thereby enabling Gα12/13-mediated RhoA signaling required for SMC proliferation and acquisition of an activated phenotype; knockdown of RGS5 blocks RhoA activation and impairs collateral growth. RGS5 overexpression, siRNA knockdown, RhoA activation assay, calcium mobilization assay, Rgs5-deficient mice, collateral arteriole growth measurement EMBO molecular medicine High 24972930
2015 GPSM3 (AGS4/G18) directly binds RGS5 selectively and enhances RGS5-mediated acceleration of GTP hydrolysis by Gαi1 in solution-based assays, while in membrane-based assays the binding of RGS5 to GPSM3 impedes GPSM3's inhibitory effect on GTP turnover. Co-immunoprecipitation, in vitro GTPase assay, membrane-based GTPase assay with M2 muscarinic receptor Molecular and cellular biochemistry Medium 25842189
2017 RGS5 localizes to and physically associates with the angiotensin II type 1 receptor (AT1R) in vascular smooth muscle cells upon AT1R activation (by AngII or mechanical stimulation), as demonstrated by proximity ligation assay; siRNA knockdown of RGS5 enhances AngII-induced constriction and myogenic responses; translocation of RGS5 to AT1R is impaired in spontaneously hypertensive rats. In situ proximity ligation assay, siRNA knockdown in intact arterioles, myogenic response measurement, candesartan competition Hypertension High 29061726
2018 Hypertensive pressure/stretch increases RGS5 expression in vascular smooth muscle cells; RGS5 is required for hypertension-induced RhoA activation and stress fiber formation through its inhibition of Gαq/11 signaling, thereby enabling the synthetic VSMC phenotype; PKC inhibition mimics RGS5-mediated effects on RhoA. Rgs5 KO mice, mechanical stretch experiments, RhoA activation assay, PKC inhibition, SMC phenotype markers FASEB journal High 29208700
2021 In the tumor microenvironment, TGFβ causes pSmad2 to bind RGS5 and traffics it to the nucleus, suppressing both RGS5-Gαi/q signaling and pSmad2/3-Smad4 pairing; this switches RGS5 from pro-apoptotic to anti-apoptotic by rescuing PI3K-AKT signaling and preventing mitochondrial damage/caspase activation in tumor pericytes. Co-immunoprecipitation, nuclear fractionation, PI3K-AKT signaling assay, apoptosis assays (Bcl2, PUMA, Bax, caspase), pericyte survival assays Cell death and differentiation High 34012071
2021 ATE1-mediated arginylation controls RGS5 turnover, which in turn regulates β-catenin stability via GSK3-β; RGS5 loss-of-function or gain-of-function modulates Wnt/β-catenin signaling in liver cancer cells, with CHIR99021 (GSK3-β inhibitor) cooperative effects confirming the pathway order. Loss- and gain-of-function (lentivirus, siRNA), co-immunoprecipitation with β-catenin, GSK3-β inhibitor epistasis Molecular cancer research Medium 34158395
2021 RGS5 overexpression in proliferating VSMCs attenuates ERK1/2 and Akt phosphorylation and promotes a resting/quiescent phenotype; selective inhibition of Gαi/o (but not Gαq/11) mimics this effect, indicating RGS5 maintains VSMC growth arrest primarily through Gαi/o suppression. RGS5 overexpression, microarray-based expression profiling, Gαi/o and Gαq/11 selective inhibitors, ERK1/2 and Akt phosphorylation assays, proliferation and migration assays Cells High 34359918
2022 RGS5 acts as a hypoxia-responsive protein in human brain pericytes that is stabilized under hypoxia independently of HIF-1α; RGS5 expression desensitizes pericytes to PDGFBB and sphingosine-1-phosphate signaling, blocking chemokinesis and chemotaxis induced by these factors. Hypoxia experiments with HIF-1α inhibition, PDGFBB/S1P chemokinesis and chemotaxis assays, RGS5 overexpression in brain pericytes Biology open Medium 36111549
2019 RGS5 inhibits calcium-sensing receptor (CASR) signaling in parathyroid cells; overexpression of RGS5 in parathyroid gland causes hyperparathyroidism, parathyroid neoplasia, and elevated PTH in transgenic mice, while RGS5-null mice have abnormally low PTH levels. Transgenic mouse overexpressing RGS5 in parathyroid, Rgs5-null mouse, CASR signaling assay in normal human parathyroid cells Journal of bone and mineral research High 30690792
2017 RGS5 inhibits Sonic Hedgehog (Shh) signaling in cortical neurons: RGS5 overexpression reduces neurite outgrowth and FM4-64 uptake (presynaptic terminal function) and affects cAMP-PKA signaling, consistent with its GAP activity on Gαi downstream of Smo. Adenoviral RGS5 overexpression in primary cortical neurons, neurite outgrowth quantification, FM4-64 uptake assay, cAMP-PKA assay Molecular and cellular neurosciences Medium 28684360
2023 RGS5 promotes neuroinflammation by binding directly to TNFR1 and TNFR2 in astrocytes, augmenting TNF signaling-mediated pro-inflammatory cytokine production; selective ablation of Rgs5 in astrocytes mitigates neuroinflammatory response in Parkinson's disease models. Astrocyte-specific Rgs5 conditional knockout, Rgs5 overexpression, Co-immunoprecipitation of RGS5 with TNFR1/TNFR2, cytokine production assays, PD animal models Journal of neuroinflammation High 37674228
2024 Age-dependent loss of RGS5 in cardiac pericytes impairs cardiac function and induces myocardial fibrosis; RGS5-deficient pericytes adopt a profibrotic gene expression signature, secreting TGFB2 and PDGFB, and the conditioned medium activates fibroblasts (αSMA induction) in a TGFβ2-dependent manner. In vivo RGS5 deletion, pericyte-fibroblast co-culture, supernatant transfer experiment, TGFβ2 neutralization, single-nucleus RNA sequencing, histological analysis Circulation research High 38563133
2006 The complex of human Gαi3 and RGS5 with GDP/Mg2+/AlF4- was crystallized at 3.0 Å resolution (space group P4(1)2(1)2, unit cell a=b=95.9 Å, c=138.8 Å), providing preliminary structural characterization of the RGS5-Gαi3 interaction. Protein overexpression in E. coli, complex crystallization, X-ray crystallography (synchrotron source) Protein and peptide letters Low 17100651
2005 A novel splice variant of RGS5 (RGS5s), lacking 108 N-terminal amino acids, localizes exclusively to the cytosolic fraction unlike full-length RGS5, and fails to inhibit Gαq-coupled AT1 or FP receptor Ca2+ signaling; co-transfection of RGS5s with RGS5 competitively blocks full-length RGS5 function. RT-PCR cloning, subcellular fractionation, Ca2+ signaling assay, co-transfection competition assay in HEK293 cells The FEBS journal Medium 15670159
2007 RGS5 forms a homodimer in addition to its monomeric form; the dimer is longer-lived than the monomer, suggesting it may serve a regulatory function in GPCR signaling. Western blot, GFP-tagged RGS5 yeast assay, two-hybrid assay, HEK293A cell analysis Cellular physiology and biochemistry Low 17762159
2012 Loss of Rgs5 in mice results in prolonged cardiac repolarization (extended QT interval and action potential duration), reduced outward voltage-dependent K+ currents (Ito, IKur, Iss), and downregulated Kv4.2, Kv4.3, Kv1.5, and Kv2.1, predisposing to ventricular tachyarrhythmia. Rgs5 KO mouse, in vivo/in vitro electrophysiology, whole-cell patch clamp, Western blot and transcript analysis of Kv channels Journal of molecular and cellular cardiology High 23079193
2023 RGS5 co-immunoprecipitates with c-Myc in gastric cancer cells and regulates c-Myc protein levels through the ubiquitin-proteasome pathway, thereby controlling mismatch repair protein expression and PD-L1 levels. Co-immunoprecipitation of RGS5 and c-Myc, ubiquitin-proteasome pathway inhibition, Western blot Molecular carcinogenesis Low 38860604

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 452 18418378
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
2003 Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells. The American journal of pathology 189 12598306
2003 Pericyte-specific expression of Rgs5: implications for PDGF and EDG receptor signaling during vascular maturation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 160 12514120
2002 Receptor-selective effects of endogenous RGS3 and RGS5 to regulate mitogen-activated protein kinase activation in rat vascular smooth muscle cells. The Journal of biological chemistry 99 12006602
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
2008 Rgs5 targeting leads to chronic low blood pressure and a lean body habitus. Molecular and cellular biology 77 18268011
2007 N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Molecular pharmacology 75 17220356
2007 RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis 70 18038251
2001 Characterization of RGS5 in regulation of G protein-coupled receptor signaling. Life sciences 70 11253162
2008 Generation and characterization of rgs5 mutant mice. Molecular and cellular biology 68 18212066
2009 RGS5, a hypoxia-inducible apoptotic stimulator in endothelial cells. The Journal of biological chemistry 61 19564336
2004 Expression of regulator of G protein signalling protein 5 (RGS5) in the tumour vasculature of human renal cell carcinoma. The Journal of pathology 61 15095478
2012 PPARγ regulates resistance vessel tone through a mechanism involving RGS5-mediated control of protein kinase C and BKCa channel activity. Circulation research 54 22962432
2007 Coexpression of Notch3 and Rgs5 in the pericyte-vascular smooth muscle cell axis in response to pulp injury. The International journal of developmental biology 53 17939118
1998 Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene. Journal of human genetics 49 9747037
2023 Resmetirom Ameliorates NASH-Model Mice by Suppressing STAT3 and NF-κB Signaling Pathways in an RGS5-Dependent Manner. International journal of molecular sciences 48 36982915
2011 Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic microenvironment. Cellular and molecular life sciences : CMLS 42 22130514
2007 Identification and characterization of T-cell epitopes deduced from RGS5, a novel broadly expressed tumor antigen. Clinical cancer research : an official journal of the American Association for Cancer Research 39 17545542
2005 Expression profiling identifies smooth muscle cell diversity within human intima and plaque fibrous cap: loss of RGS5 distinguishes the cap. Arteriosclerosis, thrombosis, and vascular biology 39 16293795
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
2021 RGS5-TGFβ-Smad2/3 axis switches pro- to anti-apoptotic signaling in tumor-residing pericytes, assisting tumor growth. Cell death and differentiation 31 34012071
2014 RGS5 promotes arterial growth during arteriogenesis. EMBO molecular medicine 31 24972930
2024 RGS5+ lymphatic endothelial cells facilitate metastasis and acquired drug resistance of breast cancer through oxidative stress-sensing mechanism. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 29 39306871
2011 The relationship between RGS5 expression and cancer differentiation and metastasis in non-small cell lung cancer. Journal of surgical oncology 29 21780128
2011 Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African-Americans. Journal of hypertension 29 21881522
2011 Origin-specific epigenetic program correlates with vascular bed-specific differences in Rgs5 expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 21965603
2007 Vascular microarray profiling in two models of hypertension identifies caveolin-1, Rgs2 and Rgs5 as antihypertensive targets. BMC genomics 29 17986358
2011 Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness. The Journal of biological chemistry 27 21278382
2008 Association of RGS2 and RGS5 variants with schizophrenia symptom severity. Schizophrenia research 27 18262772
2012 Absence of Rgs5 prolongs cardiac repolarization and predisposes to ventricular tachyarrhythmia in mice. Journal of molecular and cellular cardiology 26 23079193
2010 Relationship between RGS5 expression and differentiation and angiogenesis of gastric carcinoma. World journal of gastroenterology 26 21105200
2005 Identification of a novel alternative splicing variant of RGS5 mRNA in human ocular tissues. The FEBS journal 25 15670159
2024 Age-Dependent RGS5 Loss in Pericytes Induces Cardiac Dysfunction and Fibrosis. Circulation research 24 38563133
2018 Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 29208700
2017 Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension. Hypertension (Dallas, Tex. : 1979) 23 29061726
2015 The pericyte antigen RGS5 in perivascular soft tissue tumors. Human pathology 20 26558691
2011 Combinational therapy of interferon-α and chemotherapy normalizes tumor vasculature by regulating pericytes including the novel marker RGS5 in melanoma. Journal of immunotherapy (Hagerstown, Md. : 1997) 20 21389866
2021 ATE1 Inhibits Liver Cancer Progression through RGS5-Mediated Suppression of Wnt/β-Catenin Signaling. Molecular cancer research : MCR 19 34158395
2018 RGS5 decreases the proliferation of human ovarian carcinoma‑derived primary endothelial cells through the MAPK/ERK signaling pathway in hypoxia. Oncology reports 19 30365142
2021 Down-regulated RGS5 by genetic variants impairs endothelial cell function and contributes to coronary artery disease. Cardiovascular research 17 31605122
2016 Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5. The Journal of pharmacology and experimental therapeutics 17 27189971
2004 Beta adrenergic receptor-mediated atrial specific up-regulation of RGS5. Life sciences 17 15680317
2023 RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling. Journal of neuroinflammation 15 37674228
2023 RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment. Biology direct 15 37986113
2020 RGS5 plays a significant role in renal cell carcinoma. Royal Society open science 15 32431860
2022 RGS5: a novel role as a hypoxia-responsive protein that suppresses chemokinetic and chemotactic migration in brain pericytes. Biology open 14 36111549
2012 Atrial tachyarrhythmia in Rgs5-null mice. PloS one 14 23144791
2023 Listeria-based vaccination against the pericyte antigen RGS5 elicits anti-vascular effects and colon cancer protection. Oncoimmunology 13 37781234
2014 Dlx1 and Rgs5 in the ductus arteriosus: vessel-specific genes identified by transcriptional profiling of laser-capture microdissected endothelial and smooth muscle cells. PloS one 13 24489801
2003 A culture device demonstrates that hydrostatic pressure increases mRNA of RGS5 in neuroblastoma and CHC1-L in lymphocytic cells. Cells, tissues, organs 13 14504426
2023 RGS5 as a Biomarker of Pericytes, Involvement in Vascular Remodeling and Pulmonary Arterial Hypertension. Vascular health and risk management 12 37881333
2007 Phosphorylation of Ser166 in RGS5 by protein kinase C causes loss of RGS function. Life sciences 12 17540411
2017 Regulator of G protein signaling 5 (RGS5) inhibits sonic hedgehog function in mouse cortical neurons. Molecular and cellular neurosciences 10 28684360
2015 MicroRNAs that target RGS5. Iranian journal of basic medical sciences 10 25810883
2021 RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells. Cells 9 34359918
2016 Ruminal expression of the NQO1, RGS5, and ACAT1 genes may be indicators of feed efficiency in beef steers. Animal genetics 9 27611366
2013 Regulator of G-protein signaling - 5 (RGS5) is a novel repressor of hedgehog signaling. PloS one 9 23637832
2019 Parathyroid-Targeted Overexpression of Regulator of G-Protein Signaling 5 (RGS5) Causes Hyperparathyroidism in Transgenic Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 8 30690792
2023 Lnc‑RGS5 sponges miR‑542‑5p to promote FoxM1/VEGFA signaling and breast cancer cell proliferation. International journal of oncology 7 37594134
2022 NLGP regulates RGS5-TGFβ axis to promote pericyte-dependent vascular normalization during restricted tumor growth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 35363396
2022 miR-320a Targeting RGS5 Aggravates Atherosclerosis by Promoting Migration and Proliferation of ox-LDL-Stimulated Vascular Smooth Muscle Cells. Journal of cardiovascular pharmacology 6 35522176
2015 Association of regulator of G protein signaling (RGS5) gene variants and essential hypertension in Mongolian and Han populations. Genetics and molecular research : GMR 6 26782409
2023 Lineage Tracing of RGS5-CreER-Labeled Cells in Long Bones During Homeostasis and Injury. Stem cells (Dayton, Ohio) 4 36888549
2000 Molecular cloning and characterization of Xenopus RGS5. Biochemical and biophysical research communications 4 10733901
2024 The mechanism of RGS5 regulating gastric cancer mismatch repair protein. Molecular carcinogenesis 3 38860604
2021 RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury. International journal of molecular sciences 3 34502263
2015 Regulation of RGS5 GAP activity by GPSM3. Molecular and cellular biochemistry 3 25842189
2012 RGS5 gene and therapeutic response to short acting bronchodilators in paediatric asthma patients. Pediatric pulmonology 3 23193110
2025 Germline deletion of Rgs2 and/or Rgs5 in male mice does not exacerbate left ventricular remodeling induced by subchronic isoproterenol infusion. Physiological reports 2 39746869
2021 Absence of Rgs5 Influences the Spatial and Temporal Fluctuation of Cardiac Repolarization in Mice. Frontiers in physiology 2 33815137
2007 Evidence for the dimerization of human regulator of G-protein signalling 5 (RGS5). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2 17762159
2025 A pan-cancer analysis of the oncogenic and immunological roles of RGS5 in clear cell renal cell carcinomas based on in vitro experiment validation. Human genomics 1 39985100
2022 Hypoxia-induced miR-182-5p regulates vascular smooth muscle cell phenotypic switch by targeting RGS5. Cell biology international 1 35946384
2020 RGS5 rs4657251 polymorphism is associated with small vessel occlusion stroke in Taiwan Han Chinese. Journal of the Chinese Medical Association : JCMA 1 32080025
2025 Overexpression of MEOX2 inhibits breast cancer cell metastasis by targeting oxidative stress-induced RGS5. In vitro cellular & developmental biology. Animal 0 40603753
2006 Expression, purification, and preliminary X-ray crystallographic analysis of the complex of G(alphai3)-RGS5 from human with GDP/Mg2+)/AlF4-. Protein and peptide letters 0 17100651