Affinage

RGS6

Regulator of G-protein signaling 6 · UniProt P49758

Length
472 aa
Mass
54.4 kDa
Annotated
2026-06-10
45 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS6 is an R7-family regulator of G-protein signaling that, in obligate complex with Gβ5, functions as a Gi/o-selective GTPase-activating protein (GAP) to accelerate deactivation of GIRK channels downstream of inhibitory GPCRs in heart and brain (PMID:12531899, PMID:20864673, PMID:20884879). Its GGL domain confers selective binding to Gβ5—mimicking canonical Gβγ pairing—and Gβ5 in turn is the principal brain partner of RGS6, with the two copurifying as a tight ~1:1 membrane complex (PMID:10339615, PMID:10648734). The isolated RGS domain encodes a two-tiered specificity mechanism in which 'disruptor' residues attenuate activity toward both Gαo and Gαi1 while a 'modulatory' residue overcomes this inhibition selectively for Gαo, biasing RGS6 toward Gαo as a substrate (PMID:31153905). In the cardiac sinoatrial node, the RGS6/Gβ5 complex terminates M2 muscarinic receptor–Gi/o–IKACh signaling, so that RGS6 loss produces exaggerated bradycardia, delayed IKACh deactivation, and arrhythmia; this Gαo preference makes RGS6 control receptor-selective, strongly shaping M2R-GIRK over A1R-GIRK dynamics (PMID:20864673, PMID:20884879, PMID:32513692). In the nervous system, RGS6/Gβ5/R7BP complexes set the kinetics of GIRK and adenylyl-cyclase responses downstream of GABAB, 5-HT1A, D2, and kappa-opioid receptors, governing motor coordination, mood, dopaminergic neuron survival, hippocampal neurogenesis, and reward/nociception behaviors (PMID:22179605, PMID:24421401, PMID:31120439, PMID:42107525). Beyond its GAP role, RGS6 uses its GGL and RGS domains to scaffold non-G-protein partners independently of GAP activity: it binds SCG10 to promote neuronal differentiation (PMID:12140291), bridges DMAP1/DNMT1 and Tip60 to control DNMT1 stability and suppress Ras-driven transformation and bladder carcinogenesis (PMID:14734556, PMID:23995786, PMID:27713144), complexes with ATM kinase and Nucleolin to drive ROS-dependent and nucleolar-stress-dependent apoptosis in liver and heart (PMID:34534913, PMID:38409136), and binds SMAD4 to inhibit TGF-β-induced EMT (PMID:35902557). RGS6 is expressed as numerous splice isoforms whose subcellular localization is governed by the GGL domain and Gβ5, with stress driving RGS-domain-dependent nucleolar trafficking (PMID:12761221, PMID:12761220).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established that RGS6 carries a GGL domain that pairs selectively with Gβ5, defining the structural basis for its obligate heterodimeric form rather than canonical Gβγ pairing.

    Evidence Co-expression/Co-IP of RGS6 with Gβ1–5 and GGL-domain mutagenesis in cells

    PMID:10339615

    Open questions at the time
    • Did not establish functional consequence of Gβ5 binding for GAP activity
    • No structural model of the GGL/Gβ5 interface
  2. 2000 High

    Showed that the RGS6/Gβ5 pairing occurs natively, identifying RGS6 as a principal brain Gβ5 partner outside the canonical Gβγ framework.

    Evidence Immunoaffinity purification of Gβ5 from mouse brain with MALDI MS and reciprocal Co-IP

    PMID:10648734

    Open questions at the time
    • Did not assign a downstream signaling role to the native complex
    • Tissue scope limited to brain
  3. 2002 High

    Demonstrated a GAP-independent scaffolding function for RGS6, the first evidence that it acts beyond G-protein regulation.

    Evidence Yeast two-hybrid, reciprocal pulldown, and PC12 differentiation assay with a GAP-dead mutant

    PMID:12140291

    Open questions at the time
    • In vitro/cell-line context only, no in vivo neuronal differentiation validation
    • Microtubule-disruption mechanism not resolved at molecular detail
  4. 2003 High

    Defined RGS6 as a Gi/o-selective GAP and mapped its splice/localization control, linking domain architecture to substrate selectivity and subcellular distribution.

    Evidence Reconstituted in vitro GTPase assays with purified Gβ5/R7 dimers; cloning of 36 transcripts with GFP imaging and stress-induced trafficking analysis

    PMID:12531899 PMID:12761220 PMID:12761221

    Open questions at the time
    • Physiological receptor context of GAP selectivity not yet tested
    • Functional role of nucleolar trafficking unknown
    • Splice-isoform-specific functions undefined
  5. 2004 High

    Identified RGS6 as a regulator of the DNMT1 transcriptional repressor complex via DMAP1 binding, expanding its non-canonical role into transcriptional control.

    Evidence Yeast two-hybrid, Co-IP from cells and native brain with GGL deletion mutants, and transcriptional reporter assay

    PMID:14734556

    Open questions at the time
    • Genes regulated by RGS6/DMAP1/DNMT1 in vivo not identified
    • Physiological significance not yet tested
  6. 2010 High

    Established the in vivo cardiac function of RGS6 as the GAP terminating M2R-Gi/o-IKACh signaling in the sinoatrial node, the first demonstration of its physiological GAP role.

    Evidence Rgs6 KO mice with in vivo, isolated-heart, and SAN/atrial myocyte patch clamp; reciprocal Co-IP from cardiac tissue (two independent labs)

    PMID:20864673 PMID:20884879

    Open questions at the time
    • Receptor selectivity of RGS6 GAP action not yet dissected
    • Did not address which Gα isoform is preferred in vivo
  7. 2011 High

    Extended RGS6's GIRK-deactivating role to brain GABAB signaling and revealed a GAP-independent pro-apoptotic ROS function, distinguishing two arms of RGS6 biology.

    Evidence Rgs6 KO mice with cerebellar granule neuron patch clamp, rotarod, and pharmacological rescue; KO MEFs and GAP-dead overexpression with mitochondrial apoptosis readouts

    PMID:21041304 PMID:22179605

    Open questions at the time
    • Source of RGS6-driven ROS not molecularly defined in 2011
    • Apoptosis pathway upstream trigger unresolved
  8. 2013 High

    Connected RGS6 to ATM/p53-mediated apoptosis and DNMT1/Tip60-mediated tumor suppression, establishing it as a scaffold integrating oxidative stress, DNA damage signaling, and oncogenic transformation.

    Evidence Rgs6 KO mice in doxorubicin cardiotoxicity model with ROS/ATM/p53 readouts; KO MEFs in Ras transformation assay with ternary complex Co-IP and acetylation/ubiquitylation assays; intrinsic heart-rate-variability and RGS4 epistasis studies

    PMID:23338613 PMID:23995786 PMID:24204714 PMID:24318880

    Open questions at the time
    • Mechanism linking ROS to ATM activation not fully resolved
    • Relative contribution of GAP vs scaffold functions to cardiac vs cancer phenotypes unclear
  9. 2014 Medium

    Broadened RGS6's neuronal GPCR regulation to 5-HT1A and dopaminergic circuits, linking it to mood behavior and dopaminergic neuron maintenance.

    Evidence Rgs6 KO mice with behavioral testing, pharmacological 5-HT1A rescue, CREB phosphorylation, and immunohistochemical/expression profiling of vSNc neurons

    PMID:24421401 PMID:25501001

    Open questions at the time
    • 5-HT1A-Gαi link inferred from receptor blockade rather than direct measurement
    • Mechanism of dopaminergic neuron degeneration correlative
  10. 2016 Medium

    Demonstrated in vivo that RGS6 loss accelerates carcinogenesis through p53 impairment and DNMT1 accumulation, validating the tumor-suppressor scaffold function pharmacologically.

    Evidence Rgs6 KO mice in BBN bladder carcinogenesis model with p53/DNMT1 immunoblotting and dual pharmacological rescue (CP-31398, 5-Aza)

    PMID:27713144

    Open questions at the time
    • Direct molecular link between RGS6 and p53 stabilization in urothelium not shown
    • Single tumor model
  11. 2019 High

    Resolved the structural basis of RGS6's Gαo-over-Gαi selectivity and tied D2 autoreceptor suppression to dopaminergic neuron survival, modeling sporadic Parkinson's hallmarks.

    Evidence In vitro GTPase assays with RGS-domain mutagenesis of disruptor/modulatory residues; Rgs6 KO mice with neuron counting, HPLC, cAMP assays, and α-synuclein staining

    PMID:31120439 PMID:31153905

    Open questions at the time
    • Structural specificity determined for isolated RGS domains, not full-length complex in vivo
    • Causal chain from D2 hyperactivity to neurodegeneration partly correlative
  12. 2020 High

    Provided the mechanistic explanation for receptor-selective RGS6 action—Gαo preference combined with receptor-biased G-protein coupling—and linked RGS6 to activity-dependent hippocampal neurogenesis.

    Evidence Fast-kinetic BRET in HEK cells, SAN patch clamp, and conditional Gαo/Gαi2 KO epistasis; retroviral RGS6 overexpression/knockdown in adult-born neurons with running paradigm

    PMID:32513692 PMID:32755589

    Open questions at the time
    • Whether scaffold functions contribute to neurogenesis not addressed
    • Receptor selectivity tested mainly in SAN/HEK contexts
  13. 2021 High

    Established a direct RGS6-ATM complex via specific RGS-domain aspartate residues, defining RGS6 as a sufficient driver of stress-dependent ATM phosphorylation and hepatocyte apoptosis.

    Evidence Liver-specific RGS6 knockdown in HFD mice, Co-IP of RGS6-ATM, RGS-domain mutagenesis disrupting ATM binding, and γH2AX/ROS/apoptosis readouts

    PMID:34534913

    Open questions at the time
    • How ATM binding is coupled to ROS amplification not fully resolved
    • Single tissue (liver)
  14. 2022 Medium

    Expanded RGS6's scaffold repertoire to SMAD4-mediated EMT suppression and documented brain-specific phospho-isoforms, refining its isoform and post-translational complexity.

    Evidence Co-IP of RGS6-SMAD4 with nuclear fractionation and EMT/metastasis assays in NSCLC; isoform-specific antibodies and phosphatase treatment in CNS tissue

    PMID:34880111 PMID:35902557

    Open questions at the time
    • Kinase/phosphatase acting on RGS6 not identified
    • Functional consequence of RGS6 phosphorylation undefined
  15. 2023 Medium

    Localized RGS6's inhibitory GPCR regulation to VTA dopamine neurons and connected it to sex-dependent alcohol consumption behavior via D2 and GABAB receptor modulation.

    Evidence Conditional VTA dopamine-neuron RGS6 KO with patch clamp and sex-stratified binge alcohol assays

    PMID:36929333

    Open questions at the time
    • Mechanistic basis of sex-dependence unresolved
    • Circuit-level consequences not mapped
  16. 2024 Medium

    Identified RGS6-Nucleolin binding as a nucleolar-stress apoptosis mechanism in cardiomyocytes and extended dopaminergic-neuron RGS6 loss to DAT regulation and altered ethanol reward.

    Evidence Co-IP of RGS6-Nucleolin with rRNA/miRNA-21 quantification, bidirectional manipulation and rescue across cardiomyocyte models and in vivo; conditional DA-neuron KO with DAT immunostaining and reward/reinstatement assays

    PMID:38409136 PMID:38856764

    Open questions at the time
    • RGS6-Nucleolin interaction interface not mapped
    • DAT regulation mechanistic link to Gαi/o inferred, not directly shown
  17. 2026 Medium

    Defined a dominant-negative brain-specific isoform (RGS6B) lacking GAP activity, adding an endogenous regulatory layer to RGS6-dependent Gαi/o control while retaining cytotoxic activity.

    Evidence Molecular cloning, siRNA depletion, cAMP assay, Co-IP, and cycloheximide chase (preprint); plus genetic dissection of RGS6's KOR-dependent, sex-dependent antinociception within the R7 family

    PMID:42107525 PMID:42182468

    Open questions at the time
    • RGS6B findings not yet peer-reviewed
    • Physiological abundance and regulation of RGS6B isoform unknown
    • Molecular basis of KOR sex-dependence unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RGS6's GAP-dependent GPCR regulation and its GAP-independent scaffold/apoptotic functions are coordinated within a single cell—and which isoforms, partners, and post-translational states route RGS6 between these roles—remains unresolved.
  • No unified model linking subcellular localization to functional switching
  • Writer/eraser for RGS6 phosphorylation unidentified
  • Structural model of full-length RGS6/Gβ5 with non-G-protein partners lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-397014 Muscle contraction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1643685 Disease 3
Partners
ATMDMAP1DNMT1GNB5KAT5NCLSCG10SMAD4
Complex memberships
RGS6/DNMT1/Tip60RGS6/Gβ5RGS6/Gβ5/R7BP

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 RGS6, as part of a Gβ5/RGS6 dimer, functions as a GTPase-activating protein (GAP) selective for Gα subunits of the Gi family (Gαo, Gαi1, Gαi2, Gαi3) but not Gαq or Gα11, with intermediate maximal GAP activity compared to other R7 family members. Gβ5/RGS6 and Gβ5/RGS7 can also inhibit Gβ5/RGS11-stimulated GTPase activity of Gαo. In vitro steady-state GTPase assay using purified Sf9 cell-derived Gβ5/R7 protein dimers reconstituted in proteoliposomes with M2 or M1 muscarinic receptor-coupled G-protein heterotrimers The Journal of biological chemistry High 12531899
1999 RGS6 contains a G protein γ-subunit-like (GGL) domain that selectively binds Gβ5 but not other Gβ subunits (Gβ1–4), mimicking canonical Gβγ pairing. Mutation of the conserved Phe-61 residue of Ggamma2 to tryptophan (the residue present in all GGL domains) increased Gβ5/Ggamma2 heterodimer stability, implicating this residue in GGL/Gβ5 association. Co-expression and co-immunoprecipitation of RGS6 with different Gβ subunits in cells; mutagenesis of GGL domain residues; alpha-helical/coiled-coil predictions correlated with functional binding assays Proceedings of the National Academy of Sciences of the United States of America High 10339615
2000 In mouse brain, Gβ5 copurifies with RGS6 and RGS7 in an approximately 1:1 ratio as tight membrane-associated complexes, with no co-purifying Gαq/11, Gαi1/2, or conventional Gγ subunits, indicating RGS6 is a principal brain binding partner of Gβ5 outside the canonical Gβγ framework. Immunoaffinity purification of Gβ5 from mouse brain membranes followed by MALDI mass spectrometry identification of co-purifying proteins; reciprocal co-immunoprecipitation of native proteins The Journal of neuroscience High 10648734
2002 RGS6 interacts with SCG10 (a neuronal growth-associated protein) via its GGL domain (the SCG10-interacting region) binding the stathmin domain of SCG10. This interaction promotes microtubule disruption and synergistically enhances NGF-induced PC12 neuronal differentiation by a mechanism independent of RGS6's GTPase-activating protein activity toward G proteins. Yeast two-hybrid mapping; co-immunoprecipitation/pulldown in COS-7 cells; co-localization in PC12/COS-7 cells; dominant-negative GAP mutant (critical G-protein-interacting residue mutated) showing neuronal differentiation is GAP-independent; PC12 differentiation assay The Journal of biological chemistry High 12140291
2003 Human RGS6 undergoes complex alternative splicing producing 36 distinct transcripts. RGS6 splice variants with complete GGL domains interact with Gβ5, while those lacking a complete GGL domain do not. The long N-terminal and GGL domain sequences act as cytoplasmic retention sequences preventing nuclear/nucleolar accumulation. Co-expression of Gβ5 promotes nuclear localization of RGS6, identifying a role for Gβ5 in controlling RGS6 subcellular distribution. Molecular cloning and sequencing of 36 transcripts; co-immunoprecipitation of RGS6 splice variants with Gβ5 in COS-7 cells; fluorescence microscopy of GFP-tagged RGS6 variants with/without Gβ5 co-expression; domain deletion analysis The Journal of biological chemistry Medium 12761221
2003 Mild heat stress, proteasome-mediated proteotoxic stress, and HSF1 expression induce dramatic relocalization of RGS6 proteins to nucleoli. The RGS domain of RGS6 is the primary structural module supporting stress-induced nucleolar trafficking. The DEP domain, but not the RGS domain, supports transcription-linked nucleolar migration. This stress-induced trafficking is not elicited by other cellular stress forms and is kinase-independent. Fluorescence microscopy of GFP-tagged RGS6 variants in COS-7 cells under heat/proteasome inhibitor/HSF1/RNA Pol I inhibitor treatments; domain deletion mutants; protein kinase inhibitors and dominant-negative kinase constructs The Journal of biological chemistry Medium 12761220
2004 RGS6 interacts with DMAP1 (a component of the Dnmt1 transcriptional repressor complex) via the N-terminal region of its GGL domain (distinct from the Gβ5-binding region), and co-immunoprecipitates Dnmt1 in a DMAP1-dependent manner. RGS6 inhibits the transcriptional repressor activity of DMAP1. Co-expression of DMAP1 promotes nuclear migration of RGS6L. Yeast two-hybrid screen; co-immunoprecipitation in COS-7 cells with GGL domain deletion mutants; pulldown of endogenous DMAP1 and Dnmt1 from neuroblastoma lysates using recombinant GGL domain; co-IP from mouse brain; transcriptional repressor reporter assay The Journal of biological chemistry High 14734556
2010 RGS6 is essential for normal parasympathetic regulation of heart rate. Loss of RGS6 in mice causes exaggerated carbachol-induced bradycardia, enhanced inhibition of spontaneous action potential firing in sinoatrial node cells, and significantly slowed activation and deactivation kinetics and reduced desensitization of acetylcholine-activated potassium current (IKACh), consistent with RGS6 functioning as a GAP to inactivate Gi/o and terminate GIRK channel signaling. RGS6 knockout mice; in vivo carbachol administration; isolated perfused heart recordings; whole-cell patch clamp of sinoatrial node cells and atrial myocytes measuring IKACh kinetics Circulation research High 20864673 20884879
2010 The cardiac RGS6/Gβ5 complex physically interacts in atrial myocytes (demonstrated by immunoprecipitation) and modulates the timing (deactivation kinetics) of muscarinic m2R-IKACh signaling; loss of Rgs6 yields profound delays in IKACh deactivation in neonatal atrial myocytes and adult sinoatrial nodal cells. Immunoblotting and immunoprecipitation from cardiac tissue; Rgs6−/− mice generated by gene targeting; whole-cell patch clamp; ECG telemetry Circulation research High 20884879
2011 RGS6 induces apoptosis in breast cancer cells and mouse embryonic fibroblasts via the intrinsic mitochondrial pathway (regulating Bax/Bcl-2, mitochondrial outer membrane permeabilization, cytochrome c release, caspase-3/9 activation) through reactive oxygen species production. This apoptotic activity does not require RGS6's GAP activity toward G proteins. RGS6 overexpression in breast cancer cell lines; RGS6−/− mouse embryonic fibroblasts; GAP-inactive RGS6 mutant; flow cytometry for apoptosis/ROS/mitochondrial membrane potential; caspase activation assays; doxorubicin challenge The Journal of biological chemistry Medium 21041304
2011 RGS6 is a key regulator of GABAB receptor signaling in cerebellum, forming a complex with Gβ5 and R7BP in cerebellar granule cells. Loss of RGS6 causes significantly delayed deactivation kinetics of baclofen-induced GIRK channel currents in cerebellar granule neurons and ataxia in mice, which is improved by a GABAR antagonist. RGS6−/− mice; immunohistochemistry and co-immunoprecipitation (RGS6/Gβ5/R7BP complex); patch clamp of cerebellar granule neurons; rotarod behavioral assay; pharmacological rescue with GABAB antagonist and baclofen challenge The Journal of biological chemistry High 22179605
2013 RGS6 mediates doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy through ROS generation and downstream ATM/p53 apoptosis signaling. RGS6−/− mice are completely protected from doxorubicin-induced left ventricular dysfunction, myocardial ROS generation, and ATM/p53 activation. RGS6−/− mice; doxorubicin administration in vivo; echocardiography; ROS measurement in ventricles and isolated ventricular myocytes; ATM/p53 pathway immunoblotting; apoptosis assays in isolated ventricular myocytes Cancer research High 23338613
2013 RGS6 suppresses Ras-induced cellular transformation by acting as a scaffolding protein that bridges Dnmt1 and Tip60, facilitating Tip60-mediated acetylation and subsequent ubiquitylation and degradation of Dnmt1. The RGS domain of RGS6 (independently of its GAP activity) is sufficient to mediate Tip60 association. RGS6−/− and wild-type mouse embryonic fibroblasts; oncogenic Ras transformation assay; Co-immunoprecipitation of RGS6/Dnmt1/Tip60 complexes; Dnmt1 acetylation and ubiquitylation assays; RGS domain truncation constructs Oncogene High 23995786
2014 RGS6 is the critical negative regulator of 5-HT1A receptor-adenylyl cyclase signaling in hippocampal and cortical neurons. Loss of RGS6 causes spontaneous anxiolytic and antidepressant behavior reversible by 5-HT1A receptor blockade, associated with decreased CREB phosphorylation implicating enhanced Gαi-dependent adenylyl cyclase inhibition. RGS6−/− mice; behavioral testing (anxiety, depression paradigms); pharmacological rescue with 5-HT1A antagonist; SSRI and 5-HT1A agonist challenge in RGS6+/− mice; CREB phosphorylation immunoblotting in hippocampus/cortex FASEB journal Medium 24421401
2013 The m2R-RGS6-IKACh pathway controls intrinsic heart rate variability independently of autonomic input. Ablation of Rgs6 results in irregular cardiac rhythmicity and increased susceptibility to atrial fibrillation in mice. Rgs6−/− mice; isolated heart preparations; single sinoatrial node cell recordings; ECG telemetry; identification of human RGS6 loss-of-function variants correlated with increased heart rate variability PloS one Medium 24204714
2013 RGS6-Gβ5, but not RGS4, is the primary RGS modulator of parasympathetic heart rate regulation and sinoatrial node M2R-IKACh signaling; concurrent ablation of RGS4 partially rescues RGS6−/− deficits, suggesting another R7 RGS protein is unmasked by RGS4 loss. Rgs4−/−, Rgs6−/−, and Rgs4−/−:Rgs6−/− double-knockout mice; isolated heart perfusion; SAN cell patch clamp; pharmacological approach in SAN cells from Rgs6−/− and Gβ5−/− mice The Journal of biological chemistry High 24318880
2014 RGS6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra compacta (vSNc). Loss of Rgs6 in mice leads to age-dependent unilateral degeneration of vSNc mDA neurons beginning at ~6 months, accompanied by reduced tyrosine hydroxylase, decreased nuclear Pitx3, and altered expression of Pitx3 target genes (Vmat2, Bdnf, Aldh1a1, Fgf10), as well as increased DAT and phospho-Erk1/2 indicating elevated dopamine signaling. Rgs6−/− mice; immunohistochemistry; flow cytometry; expression profiling; TH/Pitx3/DAT/pErk1-2 immunostaining; neuron counting and morphological analysis PLoS genetics Medium 25501001
2016 RGS6 loss impairs p53 activation and promotes aberrant accumulation of oncogenic DNMT1 in urothelium, accelerating carcinogen (BBN)-induced bladder carcinogenesis. Restoration of p53 (CP-31398) or DNMT1 inhibition (5-Aza) protects RGS6−/− mice from BBN-induced tumorigenesis. RGS6−/− mice; BBN carcinogenesis model; p53 and DNMT1 immunoblotting in urothelium; pharmacological rescue with CP-31398 and 5-Aza; pathological staging of bladder lesions Oncotarget Medium 27713144
2019 RGS6 critically suppresses D2 autoreceptor-Gαi/o signaling in substantia nigra dopamine neurons, promoting neuronal survival. RGS6−/− mice exhibit hyperactive D2 autoreceptors with reduced cAMP signaling, SNc dopamine neuron loss, reduced nigrostriatal dopamine, motor deficits, and α-synuclein accumulation, recapitulating sporadic Parkinson's hallmarks. RGS6−/− mice; stereological neuron counting; HPLC for dopamine; cAMP signaling assays in SNc neurons; α-synuclein immunostaining; motor behavioral testing; immunohistochemistry in human Parkinson's tissue JCI insight Medium 31120439
2019 The isolated RGS domains of RGS6 and RGS7 are sufficient to discriminate between Gαo and Gαi1 via a two-tiered specificity mechanism: non-specific 'disruptor residues' attenuate RGS activity toward both Gα subunits, but a unique 'modulatory residue' specifically overcomes this inhibition toward Gαo, conferring Gαo preference. In vitro GTPase assays with RGS domain constructs; site-directed mutagenesis of disruptor and modulatory residues; insertion of identified residues into a high-activity RGS scaffold Journal of molecular biology High 31153905
2020 RGS6 modulates GPCR-dependent GIRK channel signaling dynamics in sinoatrial node cells in a receptor-selective manner: it suppresses M2R-GIRK coupling efficiency/kinetics and A1R-GIRK signaling amplitude. BRET assays showed RGS6 prefers Gαo over Gαi as a GAP substrate, and M2R signals preferentially via Gαo while A1R does not discriminate, explaining receptor-selective RGS6 influence. Rgs6−/− mice; patch clamp of SAN cells; fast kinetic BRET assays in transfected HEK cells; Gαo- and Gαi2-selective conditional knockout mice in atrium/SAN Proceedings of the National Academy of Sciences of the United States of America High 32513692
2020 RGS6 mediates voluntary running-induced adult hippocampal neurogenesis and its associated learning and anxiolytic effects. RGS6 overexpression mimics running-induced morphological and physiological maturation of adult-born neurons, including reduced sensitivity to GABAB receptor inhibition. RGS6 knockdown abolishes running-enhanced neuronal maturation and neurogenesis-dependent learning. Voluntary running wheel paradigm; retroviral RGS6 overexpression and shRNA knockdown in adult-born hippocampal neurons; morphological analysis; electrophysiology of adult-born neurons; behavioral testing (learning, anxiety) Cell reports Medium 32755589
2021 In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain, and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation and subsequent hepatocyte apoptosis. RGS6 also promotes ROS generation and acts as an amplification node for oxidative stress. RGS6 mutants lacking ATM-binding capacity fail to facilitate palmitic acid-dependent hepatocyte apoptosis. Liver-specific RGS6 knockdown in HFD-fed mice; co-immunoprecipitation of RGS6-ATM complex; RGS domain mutagenesis (aspartate residues) disrupting ATM binding; ATM phosphorylation and DNA damage marker (γH2AX) assays; ROS measurement; hepatocyte apoptosis assay with palmitic acid Redox biology High 34534913
2022 RGS6 phosphorylation exists in brain: a 65-kDa phosphorylated RGS6 isoform and its dephospho form (69-kDa) were identified as brain-specific, with the 69-kDa band being a dephosphorylated form of the 65-kDa band. Novel isoform-specific antibodies (anti-RGS6-fl, anti-RGS6-L, anti-RGS6-18); immunoblotting across mouse CNS and peripheral tissues; phosphatase treatment distinguishing phospho from dephospho forms eNeuro Medium 34880111
2022 RGS6 suppresses TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancer by binding SMAD4, preventing SMAD4-SMAD2/3 complex formation, reducing nuclear entry of phospho-SMAD3 and SMAD4, and thereby impairing downstream SMAD3-mediated gene expression. This function is independent of RGS6's regulation of G-protein signaling. Co-immunoprecipitation of RGS6-SMAD4 interaction; RGS6 overexpression in NSCLC cells; TGF-β-induced EMT assays (E-cadherin, vimentin, N-cadherin); nuclear fractionation for SMAD3/SMAD4; in vivo metastasis model; G-protein signaling independence verified Cell death & disease Medium 35902557
2024 RGS6 binds to Nucleolin in cardiomyocytes and suppresses Nucleolin expression, phosphorylation, and its effector miRNA-21, driving nucleolar stress-dependent cardiomyocyte apoptosis (including suppression of ribosomal RNA production). Doxorubicin increases the RGS6/Nucleolin ratio in heart. Overexpression of Nucleolin or miRNA-21 counteracts RGS6-induced apoptosis. Co-immunoprecipitation of RGS6-Nucleolin complex; RGS6 overexpression/knockdown in AC-16 cells, iPSC-derived cardiomyocytes, and primary murine cardiomyocytes; ribosomal RNA quantification; miRNA-21 measurement; intracardiac RGS6-shRNA injection in mice; human cardiac tissue immunoblotting Journal of translational medicine Medium 38409136
2023 RGS6 is expressed in VTA dopamine neurons and modulates inhibitory G protein signaling in a receptor-dependent manner, tempering D2 receptor-induced somatodendritic currents and accelerating deactivation of synaptically evoked GABAB receptor-dependent responses. Loss of RGS6 in VTA dopamine neurons (via conditional knockout) reduces binge-like alcohol consumption in female but not male mice. RGS6−/− mice; conditional VTA dopamine neuron-specific RGS6 KO (RGS6fl/fl; DAT-iCreER); patch clamp electrophysiology in VTA dopamine neurons; binge alcohol consumption assay; sex-stratified analysis British journal of pharmacology Medium 36929333
2024 RGS6 loss in DA neurons upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals and reduces ethanol consumption, preference, reward, and relapse reinstatement. RGS6 is proposed to promote DA transmission by suppressing GPCR-Gαi/o-DAT signaling in VTA DA neurons. Conditional RGS6 KO in DA neurons (RGS6fl/fl; DAT-iCreER); DAT immunostaining in VTA terminals; ethanol consumption/preference assays; conditioned place preference; extinction/reinstatement paradigm Psychopharmacology Medium 38856764
2026 A brain-specific RGS6 isoform (RGS6B, ~69 kDa) was cloned; it lacks functional GAP activity toward Gαi/o and instead acts in a dominant-negative manner to block Gαi/o regulation by canonical RGS6L. RGS6B stabilizes binding partners R7BP and Gβ5 and has an increased protein half-life relative to RGS6L. It retains non-canonical cytotoxic activity against glioblastoma cells. Molecular cloning, siRNA depletion, cAMP assay, Co-IP, cycloheximide chase, cell viability assay bioRxivpreprint Medium 42182468
2026 RGS6 regulates kappa opioid receptor (KOR)-dependent antinociception in a sex-dependent manner; RGS6−/− mice show enhanced KOR-mediated antinociception and blunted nocifensive behaviors, an effect highly specific to RGS6 within the R7 RGS family and not compensated by other R7 members. Global RGS6−/− and R7 family member single/double knockout mice; KOR agonist administration (including peripherally restricted agonists); nociception behavioral assays; sex-stratified analysis Neuropharmacology Medium 42107525

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity. The Journal of biological chemistry 127 12531899
1999 Fidelity of G protein beta-subunit association by the G protein gamma-subunit-like domains of RGS6, RGS7, and RGS11. Proceedings of the National Academy of Sciences of the United States of America 101 10339615
2010 RGS6, a modulator of parasympathetic activation in heart. Circulation research 98 20864673
2010 RGS6/Gβ5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate. Circulation research 81 20884879
2000 Copurification of brain G-protein beta5 with RGS6 and RGS7. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 10648734
2013 G-protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin. Cancer research 60 23338613
2003 Human RGS6 gene structure, complex alternative splicing, and role of N terminus and G protein gamma-subunit-like (GGL) domain in subcellular localization of RGS6 splice variants. The Journal of biological chemistry 58 12761221
2002 RGS6 interacts with SCG10 and promotes neuronal differentiation. Role of the G gamma subunit-like (GGL) domain of RGS6. The Journal of biological chemistry 56 12140291
2004 A functional polymorphism in RGS6 modulates the risk of bladder cancer. Cancer research 55 15375002
2004 RGS6 interacts with DMAP1 and DNMT1 and inhibits DMAP1 transcriptional repressor activity. The Journal of biological chemistry 54 14734556
2010 Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity. The Journal of biological chemistry 50 21041304
2014 Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 24421401
2011 Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling. The Journal of biological chemistry 45 22179605
2013 RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis. Oncogene 42 23995786
2003 Mild heat and proteotoxic stress promote unique subcellular trafficking and nucleolar accumulation of RGS6 and other RGS proteins. Role of the RGS domain in stress-induced trafficking of RGS proteins. The Journal of biological chemistry 40 12761220
2014 Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra. PLoS genetics 39 25501001
2013 Essential role of the m2R-RGS6-IKACh pathway in controlling intrinsic heart rate variability. PloS one 37 24204714
2016 RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer. The AAPS journal 32 27002730
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
2020 RGS6 Mediates Effects of Voluntary Running on Adult Hippocampal Neurogenesis. Cell reports 30 32755589
2016 RGS6 is an essential tumor suppressor that prevents bladder carcinogenesis by promoting p53 activation and DNMT1 downregulation. Oncotarget 27 27713144
2021 Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death. Redox biology 24 34534913
2019 Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice. JCI insight 23 31120439
2020 GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells. Proceedings of the National Academy of Sciences of the United States of America 19 32513692
2022 RGS6 suppresses TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancers via a novel mechanism dependent on its interaction with SMAD4. Cell death & disease 16 35902557
2011 RGS6 variants are associated with dietary fat intake in Hispanics: the IRAS Family Study. Obesity (Silver Spring, Md.) 16 21233807
2015 Two for the Price of One: G Protein-Dependent and -Independent Functions of RGS6 In Vivo. Progress in molecular biology and translational science 14 26123305
2023 RGS6 negatively regulates inhibitory G protein signaling in dopamine neurons and positively regulates binge-like alcohol consumption in mice. British journal of pharmacology 13 36929333
2022 Protein Profiling of RGS6, a Pleiotropic Gene Implicated in Numerous Neuropsychiatric Disorders, Reveals Multi-Isoformic Expression and a Novel Brain-Specific Isoform. eNeuro 12 34880111
2019 RGS6 and RGS7 Discriminate between the Highly Similar Gαi and Gαo Proteins Using a Two-Tiered Specificity Strategy. Journal of molecular biology 10 31153905
2014 RGS6: a novel gene associated with congenital cataract, mental retardation, and microcephaly in a Tunisian family. Investigative ophthalmology & visual science 8 25525169
2022 RGS6 Drives Spinal Cord Injury by Inhibiting AMPK Pathway in Mice. Disease markers 7 35510037
2018 The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. PloS one 7 29668674
2017 Interaction between the RGS6 gene and psychosocial stress on obesity-related traits. Endocrine journal 7 28090039
2024 RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21. Journal of translational medicine 6 38409136
1999 The human regulator of G-protein signaling protein 6 gene (RGS6) maps between markers WI-5202 and D14S277 on chromosome 14q24.3. Journal of human genetics 5 10083744
2017 HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6. PloS one 4 28665981
2024 A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms. Journal of human genetics 2 38332109
2024 Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse. Psychopharmacology 2 38856764
2023 RGS6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in an Alzheimer's mouse model. bioRxiv : the preprint server for biology 2 39185171
2023 Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse. bioRxiv : the preprint server for biology 1 37961154
2018 Correction: The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. PloS one 1 29979785
2026 RGS6 regulates Kappa opioid receptor-mediated antinociceptive behaviors. Neuropharmacology 0 42107525
2026 Molecular cloning of a novel, nervous system-specific RGS6 isoform lacking canonical G protein regulatory effects and with dominant negative actions. bioRxiv : the preprint server for biology 0 42182468
2025 A Multimodal Atlas Reveals the Anatomical Distribution of Medium Spiny Neuron Subtypes and a Novel RGS6+ Population in the Primate Striatum. bioRxiv : the preprint server for biology 0 41332519

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