Affinage

RGS7

Regulator of G-protein signaling 7 · UniProt P49802

Length
495 aa
Mass
57.7 kDa
Annotated
2026-04-28
66 papers in source corpus 42 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS7 is a GTPase-activating protein (GAP) for Gi/o-family Gα subunits that functions as an obligatory heterodimer with Gβ5 to terminate GPCR signaling and shape the kinetics of downstream effector channels in the nervous system. The GGL domain mediates Gβ5 binding, which reciprocally stabilizes both proteins against proteasomal degradation, while the RGS domain harbors intrinsic selectivity for Gαo over Gαi through a two-tier mechanism involving disruptor and modulatory residues (PMID:10942773, PMID:31153905). Plasma membrane targeting—essential for GAP function—is achieved by palmitoylated R7BP or the orphan receptor GPR158, whose cryo-EM structures reveal that the DHEX domain of RGS7 docks to GPR158 intracellular loops while GPR158 allosterically enhances catalytic activity (PMID:15897264, PMID:34793198, PMID:25792749). In hippocampal neurons, RGS7 accelerates GABAB-GIRK current deactivation to control neuronal excitability, learning, and memory; in the retina it cooperates with RGS11 to set the speed of mGluR6-mediated light responses; and in cardiac and hepatic contexts it forms non-canonical complexes with CaMKII, Tip60, SIRT1, and ATF3 that drive oxidative stress, NF-κB acetylation, and inflammation (PMID:24755289, PMID:22547806, PMID:36574707, PMID:35521658).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1998 High

    Identification of Gβ5 as an obligate partner resolved how R7-family RGS proteins differ from other RGS proteins: the GGL domain of RGS7 mediates a tight, specific complex with Gβ5, and this interaction modulates Gαo binding.

    Evidence Native purification from bovine retina, in vitro reconstitution, domain deletion mutagenesis

    PMID:10051672 PMID:9731233

    Open questions at the time
    • Whether Gβ5 binding inhibits or redirects GAP activity in vivo was unresolved
    • Structural basis of GGL-Gβ5 interface not yet determined
  2. 1999 High

    Discovery that RGS7 is a short-lived proteasomal substrate whose stability is regulated by polycystin (PKD1) and by TNF-α/p38 MAPK signaling established protein turnover as a major regulatory axis controlling RGS7 abundance in vivo.

    Evidence Proteasome inhibitor assays, p38 kinase activation, PKD1 co-IP, TNF receptor 1 KO mice

    PMID:10339594 PMID:10426315

    Open questions at the time
    • Direct phosphorylation sites on RGS7 responsible for p38-mediated stabilization not fully mapped
    • Relationship between polycystin and Gβ5-mediated stabilization unclear
  3. 1999 High

    Functional characterization of RGS7 in GIRK channel modulation and Gα binding specificity showed it accelerates channel activation but is a weaker deactivation accelerator than RGS8, with preferential binding to Gαo, Gαi3, and Gαz.

    Evidence Xenopus oocyte GIRK electrophysiology, recombinant protein binding assay

    PMID:10092682

    Open questions at the time
    • Why deactivation acceleration is weaker than other RGS proteins was mechanistically unexplained
    • Contribution of Gβ5 to channel kinetics not tested
  4. 2000 High

    Demonstration that Gβ5 and RGS7 exist exclusively as obligatory heterodimers in brain, with mutual stabilization preventing proteasomal degradation, established the dimer as the functional unit; palmitoylation of RGS7 was linked to membrane association, and the isolated RGS domain confirmed intrinsic Gαo selectivity.

    Evidence Brain co-purification, co-expression stability assays, [³H]-palmitate labeling, stopped-flow GTPase kinetics

    PMID:10840031 PMID:10942773 PMID:11032900

    Open questions at the time
    • Identity of the palmitoyl transferase unknown
    • Whether Gβ5 restricts or refines Gα selectivity in native neurons untested
  5. 2003 High

    Reconstituted proteoliposome assays and live-cell FRET established that Gβ5-RGS7 functions as a GAP for Gi family (not Gq/G11) subunits in a lipid bilayer context, while also physically interacting with Gαq in cells to inhibit Gq-mediated calcium signaling.

    Evidence Proteoliposome GTPase assay with purified proteins, FRET with YFP/CFP-tagged proteins, Ca²⁺ assay

    PMID:12531899 PMID:12670932

    Open questions at the time
    • Mechanism of Gαq inhibition without classical GAP activity for Gq unclear
    • Relative importance of Gi vs Gq regulation in native neurons unknown
  6. 2004 High

    The C. elegans ortholog RGS-7 was placed into a receptor-independent Gαo GTPase cycle that controls asymmetric spindle positioning, revealing a conserved non-canonical role for the RGS7 family beyond GPCR signal termination; concurrently, Gαo was shown to promote RGS7 palmitoylation and membrane recruitment via the DEP domain.

    Evidence Genetic epistasis in C. elegans, in vitro GTPase assay, mutagenesis of palmitoylation and DEP domain residues in HEK293 cells

    PMID:15479638 PMID:15496508

    Open questions at the time
    • Whether spindle-positioning function is conserved in vertebrates untested
    • Palmitoyl transferase identity still unknown
  7. 2005 High

    Discovery of R7BP as a palmitoylated membrane anchor resolved how cytosolic Gβ5-RGS7 reaches the plasma membrane to regulate GPCRs: palmitoylated R7BP targets the complex to the membrane and dramatically augments GIRK regulation, while depalmitoylation drives nuclear translocation.

    Evidence Palmitoylation assay, live-cell imaging, GIRK electrophysiology, subcellular fractionation

    PMID:15897264 PMID:16867977

    Open questions at the time
    • Nuclear function of depalmitoylated R7BP-RGS7 complex unknown
    • Enzyme mediating R7BP depalmitoylation not identified
  8. 2007 High

    Intramolecular DEP-Gβ5 interaction revealed a conformational switch (open/closed states) that gates receptor subtype selectivity; direct binding of the DEP domain to the M3R third intracellular loop established the first mechanism by which an RGS protein recognizes a specific receptor.

    Evidence FRET, GST pulldown with receptor i3 loop, site-directed mutagenesis, Ca²⁺ mobilization assay

    PMID:17511476 PMID:19182865

    Open questions at the time
    • Whether other GPCRs are similarly recognized by the DEP domain unknown
    • Structural basis of DEP-receptor interaction not determined
  9. 2011 High

    Identification of DHHC2 as the palmitoyltransferase for R7BP, with Gi/o signaling inhibiting depalmitoylation, established a feedback loop: active Gi/o stabilizes the membrane GAP complex that terminates its own signaling.

    Evidence [³H]-palmitate metabolic labeling, DHHC2 siRNA, subcellular fractionation, pertussis toxin

    PMID:21343290

    Open questions at the time
    • Identity of the thioesterase mediating R7BP depalmitoylation unknown
    • Whether this feedback operates in all neuronal subtypes untested
  10. 2012 High

    Discovery that orphan receptors GPR158 and GPR179 serve as alternative membrane anchors for RGS7 complexes explained R7BP-independent membrane targeting in retina; GPR179 loss causes night blindness by mislocalizing RGS7, and concurrent RGS7/RGS11 knockout severely impairs rod ON bipolar cell light responses.

    Evidence Co-IP, KO mouse models (GPR179, RGS7, RGS11), electroretinography, patch-clamp

    PMID:22547806 PMID:22689652

    Open questions at the time
    • Whether GPR158 vs GPR179 confer distinct functional properties to the complex was unresolved
    • Mechanism by which GPR158/179 selectivity for specific R7-family members arises unknown
  11. 2014 High

    Hippocampal RGS7 knockout demonstrated that RGS7 is the dominant GAP controlling GABAB-GIRK signaling kinetics in CA1 pyramidal neurons: its loss sensitizes GIRK responses, slows deactivation, reduces excitability, and impairs learning and memory.

    Evidence RGS7 KO mice, whole-cell patch-clamp in hippocampal slices, behavioral testing

    PMID:24755289

    Open questions at the time
    • Relative contributions of R7BP vs GPR158 complexes to hippocampal function unclear
    • Whether RGS7 loss affects other hippocampal GPCR-effector pathways untested
  12. 2015 High

    GPR158 was established as essential for brain RGS7 expression and membrane localization: GPR158 knockout causes post-transcriptional loss of RGS7, and GPR158's C-terminus allosterically enhances RGS7 GAP activity through a mechanism distinct from simple membrane anchoring.

    Evidence GPR158 KO mice, in vitro GTPase assay, domain mutagenesis, co-IP

    PMID:25792749

    Open questions at the time
    • Signal that activates GPR158 unknown (orphan receptor)
    • Whether allosteric enhancement involves conformational change in RGS domain untested
  13. 2016 High

    RGS7 homo-oligomerization via the DEP domain was discovered as a new regulatory mechanism: R7BP inhibits and active Gαo prevents oligomerization, while GPR158 can accommodate the oligomer, suggesting context-dependent quaternary structure regulation.

    Evidence In situ cross-linking, mass spectrometry, co-IP of differentially tagged RGS7

    PMID:26895961

    Open questions at the time
    • Functional consequence of homo-oligomerization on GAP activity unknown
    • Stoichiometry and structure of the oligomer not determined
  14. 2018 High

    Crystal structure of the RGS7-Gβ5-R7BP ternary complex revealed the structural basis of allosteric regulation, with long-range conformational changes linking the R7BP binding site to the catalytic RGS domain through synergistic intermolecular interfaces.

    Evidence X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, molecular dynamics

    PMID:30540250

    Open questions at the time
    • Structure with Gα substrate not captured
    • How DEP domain conformational switching maps onto the crystal structure unclear
  15. 2018 High

    Functional dissection of hippocampal R7BP- vs GPR158-containing complexes revealed that only R7BP-complexes accelerate GIRK and CaV2 channel kinetics, whereas GPR158-complexes serve a distinct role in chronic stress-induced suppression of cAMP signaling in prefrontal cortex, with RGS7 loss producing antidepressant-like phenotypes.

    Evidence KO mice, quantitative biochemistry, patch-clamp in slices, behavioral assays, viral re-expression

    PMID:30315127 PMID:30546127

    Open questions at the time
    • Ligand for GPR158 that triggers stress-dependent RGS7 recruitment unknown
    • Circuit-level mechanisms connecting RGS7-mediated cAMP regulation to depression behavior unclear
  16. 2019 High

    A two-tier selectivity mechanism was elucidated: three 'disruptor' residues in the RGS domain non-specifically attenuate Gα interaction, while a unique 'modulatory' residue bypasses this inhibition specifically toward Gαo, explaining the longstanding Gαo preference.

    Evidence Systematic site-directed mutagenesis, in vitro GTPase assay

    PMID:31153905

    Open questions at the time
    • Whether this selectivity mechanism is overridden by accessory subunits in vivo untested
    • No crystal structure of RGS7 RGS domain bound to Gαo
  17. 2021 High

    Cryo-EM structures of GPR158 alone and in complex with RGS7-Gβ5 revealed the unique architecture: GPR158 dimerizes via PAS-fold and TM domains stabilized by phospholipids, and the DHEX domain of RGS7 docks to ICL2/ICL3/TM3 of GPR158, explaining receptor selectivity for RGS7.

    Evidence Single-particle cryo-EM, independently solved by two groups

    PMID:34793198 PMID:34815401

    Open questions at the time
    • Conformational changes upon G protein engagement not captured
    • Whether phospholipid identity regulates complex assembly unknown
  18. 2021 High

    Arginyltransferase Ate1 was identified as a facilitator of RGS7 proteasomal degradation, establishing an N-end rule-like pathway; Ate1 knockout elevates RGS7 in retinal ON bipolar cells and increases light sensitivity.

    Evidence Conditional Ate1 KO mouse, electroretinography, proteasome inhibition in MEFs

    PMID:33931669

    Open questions at the time
    • Whether Ate1 directly arginylates RGS7 or acts indirectly unknown
    • Relationship between Ate1 and Gβ5/GPR158-mediated stabilization unclear
  19. 2022 High

    Non-canonical roles were established in cardiac and hepatic tissues: RGS7 complexes with CaMKII to promote oxidative stress and doxorubicin cardiotoxicity, and with ATF3/Tip60 to drive TNFα release and NAFLD-associated fibrosis, expanding RGS7 function beyond classical GPCR-GAP activity.

    Evidence Co-IP with mutagenesis, cardiac/hepatic-specific KD/OE in mice, ROS and cytokine assays, high-fat diet model

    PMID:35521658 PMID:36574707

    Open questions at the time
    • Whether CaMKII and ATF3/Tip60 interactions require Gβ5 unknown
    • GAP-dependent vs GAP-independent contributions not fully separated in vivo
  20. 2023 High

    RGS7 was found to scaffold Tip60 and SIRT1 in cardiomyocytes, controlling acetylation of NF-κB p65 to drive inflammation; pharmacological modulation of this axis mitigated cardiac damage.

    Evidence Co-IP (RGS7-Tip60-SIRT1), p65 acetylation assay, Tip60 inhibitor/SIRT1 activator, cardiac RGS7 OE mice

    PMID:37589751

    Open questions at the time
    • How RGS7 simultaneously engages both Tip60 and SIRT1 structurally is unknown
    • Whether this scaffolding is relevant in non-cardiac tissues untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the endogenous ligand for GPR158 that regulates RGS7 membrane recruitment under stress; whether non-canonical cardiac/hepatic scaffolding functions require Gβ5 and/or GAP activity; and the structural basis of DEP domain-GPCR recognition.
  • GPR158 ligand identity unknown
  • No structure of RGS7 DEP domain bound to a receptor intracellular loop
  • GAP-dependent vs GAP-independent roles not genetically separated in cardiac/hepatic contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 10 GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 12 R-HSA-112316 Neuronal System 5 R-HSA-392499 Metabolism of proteins 3
Partners
ATF3CAMK2AGNAO1GNB5GPR158KAT5RGS7BPSIRT1
Complex memberships
GPR158-Gβ5-RGS7Gβ5-RGS7Gβ5-RGS7-R7BP

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Gbeta5 forms a tight complex with RGS7 in the retina; the Ggamma-like (GGL) domain of RGS7 mediates binding to Gbeta5, and deletion of this domain prevents Gbeta5 binding while retaining Galpha interaction; Gbeta5 binding to RGS7 blocks RGS7 interaction with Galphao. Native protein purification from bovine retina, in vitro reconstitution with recombinant proteins, gel filtration, ion-exchange chromatography, immunoprecipitation, domain deletion mutagenesis Proceedings of the National Academy of Sciences / Biochemical and Biophysical Research Communications High 10051672 9731233
1999 RGS7 is a short-lived protein degraded via the proteasome pathway; interaction with the C-terminal domain of polycystin (PKD1 gene product) inhibits proteasomal degradation of RGS7 and promotes its relocalization to the membrane. Proteasome inhibitor treatment, co-immunoprecipitation, subcellular localization by transfection/imaging Proceedings of the National Academy of Sciences High 10339594
1999 TNF-alpha prevents proteasome-dependent degradation of RGS7 via activation of the stress-activated protein kinase p38, requiring candidate MAPK phosphorylation sites on RGS7; in vivo, RGS7 is rapidly upregulated in mouse brain after endotoxin or TNF-alpha exposure. Proteasome inhibitor assays, p38 kinase activation, site-directed mutagenesis of phosphorylation sites, in vivo mouse model with TNF receptor 1 knockout Nature medicine High 10426315
1999 The GGL domains of RGS6, RGS7, and RGS11 selectively bind Gbeta5 but not other Gbeta subunits; Phe-61 of Ggamma2, when mutated to tryptophan (the residue in GGL domains), increases Gbeta5/Ggamma2 heterodimer stability, revealing the structural basis of GGL/Gbeta5 specificity. Co-expression with different Gbeta subunits, immunoprecipitation, mutagenesis of Ggamma residues Proceedings of the National Academy of Sciences High 10339615
1999 RGS7 accelerates activation kinetics of GIRK channels similarly to RGS8, but its acceleration of deactivation is significantly weaker; RGS7 recombinant protein binds preferentially to Galphao, Galphai3, and Galphaz. Xenopus oocyte electrophysiology, co-expression of GIRK1/2 with RGS7, recombinant protein binding assay The Journal of biological chemistry High 10092682
2000 Gbeta5 and RGS7 exist exclusively as obligatory heterodimers in brain; co-expression of Gbeta5 dramatically increases RGS7 protein levels (and vice versa) through a non-transcriptional mechanism based on increased protein stability upon dimerization; native Gbeta5-RGS7 does not co-purify with Galphao or Galphaq, yet Gbeta5-RGS7 inhibits Galphaq-mediated Ca2+ signaling in transfected cells. Immunoprecipitation, co-purification from brain, COS-7 cell co-expression, conventional chromatography, Ca2+ signaling assay The Journal of biological chemistry High 10840031
2000 RGS7 is palmitoylated on membrane-bound but not cytosolic fractions; palmitoylation does not prevent RGS7/Galphao interactions; the isolated RGS domain of RGS7 selectively binds activated Galpha(i/o) and stimulates GTPase activity; the RGS7/Gbeta5 complex selectively interacts with Galphao (not Galphai1), indicating Gbeta5 association restricts Galpha selectivity. Metabolic labeling with [3H]-palmitate, subcellular fractionation, in vitro GTPase assay, pulldown from brain extracts Journal of neurochemistry High 11032900
2000 RGS7 RGS box domain (aa 305-453) enhances Galphao GTPase deactivation with catalytic efficiency of 0.44×10^6 M^-1s^-1, preferring Galphao over Galphai2 and Galphai1; specificity for Galphao resides in the RGS domain itself, independent of N- or C-terminal extensions or Gbeta5. Stopped-flow spectroscopy measuring intrinsic tryptophan fluorescence, GST-RGS domain fusion proteins, kinetic analysis The Journal of biological chemistry High 10942773
2003 Gbeta5/RGS7 stimulates GTPase activity of Gi family Galpha subunits (but not Galphaq or Galpha11) in proteoliposomes; Gbeta5/RGS9 and Gbeta5/RGS11 are more potent GAPs for Galphai1/i2/i3 than Gbeta5/RGS7; Gbeta5/RGS7 and Gbeta5/RGS9 can inhibit Gbeta5/RGS11-stimulated GTPase activity of Galphao. Purified Sf9-derived proteins, steady-state GTPase assay in proteoliposomes with reconstituted receptor-G protein heterotrimers The Journal of biological chemistry High 12531899
2003 The Gbeta5-RGS7 complex interacts directly with Galphaq in living cells via FRET; this interaction occurs intracellularly and the complex inhibits Galphaq-mediated Ca2+ signaling. FRET spectroscopy and microscopy with YFP/CFP-tagged proteins in transfected mammalian cells, co-immunoprecipitation The Journal of biological chemistry High 12670932
2004 In C. elegans, RGS-7 (ortholog of vertebrate RGS7) localizes to the cell cortex and its RGS domain stimulates GTP hydrolysis by Galphao; RGS-7 completes a receptor-independent G protein cycle required for asymmetric mitotic spindle positioning, acting downstream of nonreceptor G protein activators RIC-8 and GPR-1/2. Genetic epistasis (C. elegans mutants), in vitro GTPase assay with recombinant RGS-7 and Galphao, live imaging of spindle movements Cell High 15479638
2004 Galphao promotes palmitoylation and plasma membrane recruitment of Gbeta5-RGS7; constitutively active Galphao (R179C) retains this ability whereas lipidation-deficient (G2A), RGS-insensitive (G184S), and inactive (G204A) Galphao mutants do not; Cys133 of RGS7 is a putative palmitoylation site; the DEP domain (aa 76-128) of RGS7 is required for Galphao-mediated membrane recruitment. Subcellular fractionation, palmitoylation assay ([3H]-palmitate labeling), site-directed mutagenesis, immunofluorescence in HEK293 cells Molecular pharmacology High 15496508
2005 R7BP (RGS7 family binding protein), a palmitoylated neuronally expressed protein, binds R7-Gbeta5 complexes and shuttles them between the plasma membrane and nucleus; palmitoylation of R7BP targets it to the plasma membrane, and depalmitoylation translocates the R7BP-R7-Gbeta5 complex to the nucleus; plasma membrane-targeted R7BP greatly augments RGS7-mediated attenuation of GPCR-activated GIRK channel activation compared to non-palmitoylated R7BP. Palmitoylation assay, subcellular fractionation, live-cell imaging, GIRK electrophysiology in HEK293 cells, co-immunoprecipitation The Journal of cell biology High 15897264
2006 R7BP augments RGS7*Gbeta5 function exclusively through a palmitoylation-regulated plasma membrane-targeting mechanism; unpalmitoylated R7BP undergoes nuclear/cytoplasmic shuttling mediated by a C-terminal polybasic motif; cytoplasmic RGS7*Gbeta5*R7BP heterotrimers and RGS7*Gbeta5 heterodimers are equivalently inefficient GPCR signaling regulators. Mutagenesis of palmitoylation sites, nuclear export inhibitor treatment, GIRK electrophysiology, subcellular fractionation The Journal of biological chemistry High 16867977
2007 The DEP domain of RGS7 interacts intramolecularly with the Gbeta5 subunit; this DEP-Gbeta5 interaction is dynamic and produces closed/open conformational states of the Gbeta5-RGS7 dimer; R7BP binding has no effect on DEP-Gbeta5 pull-down; mutation of RGS7 Glu-73/Asp-74 to Ser/Gly (ED/SG) diminishes the DEP-Gbeta5 interaction and alters M3R signaling regulation in the presence of R7BP. GST pulldown, co-immunoprecipitation, FRET with CFP/YFP-tagged proteins, site-directed mutagenesis, Ca2+ mobilization assay Biochemistry High 17511476
2008 RGS7/Gbeta5 complex is specifically targeted to the dendritic tips of ON-bipolar cells; this targeting occurs independently of R7BP association, revealing an adapter-independent targeting mechanism. In vivo mouse knockout of R7BP, immunofluorescence confocal microscopy of retinal sections The Journal of neuroscience High 18842904
2008 Intracellular administration of RGS7 via patch clamp electrodes into locus coeruleus neurons mimics chronic stress-induced decrease in alpha2-autoreceptor (clonidine-evoked) inhibition, demonstrating that elevated RGS7 reduces autoreceptor coupling. In vivo/in vitro single-unit recordings, patch-clamp intracellular RGS7 delivery, chronic cold stress model The European journal of neuroscience Medium 18461718
2009 The DEP domain of RGS7 directly binds the third intracellular loop (i3) of the M3 muscarinic receptor; the DEP domain alone is sufficient to inhibit M3R signaling; deletion of the i3 loop or DEP domain abolishes this inhibition; the C-terminus of M3R also interacts with Gbeta5-RGS7 and is required for inhibition of full-length receptor by wild-type (but not open-mutant) Gbeta5-RGS7. GST pulldown with recombinant i3 loop peptide, Ca2+ mobilization assay, domain deletion mutagenesis, truncation mutants Biochemistry High 19182865 20443543
2009 R7BP complexes differentially regulate RGS7 and RGS9-2 in the striatum; striatum-specific knockdown revealed that sensitivity of cocaine-induced motor stimulation depends on RGS7 (not RGS9-2), whose complex formation with R7BP is dictated by RGS9-2 expression levels. Striatum-specific RNAi knockdown in mice, locomotor behavior assays, biochemical analysis of complex formation Neuropsychopharmacology Medium 20043004
2011 R7BP undergoes dynamic, signal-regulated palmitate turnover; the palmitoyltransferase DHHC2 mediates de novo and turnover palmitoylation of R7BP; DHHC2 silencing redistributes R7BP from the plasma membrane to the nucleus; Gi/o signaling inhibits R7BP depalmitoylation, stabilizing membrane association of R7-Gbeta5 GAP complexes. [3H]-palmitate metabolic labeling, DHHC2 siRNA silencing, subcellular fractionation, pertussis toxin treatment The Journal of biological chemistry High 21343290
2012 GPR158 and GPR179 recruit RGS7 complexes to the plasma membrane and augment their ability to regulate GPCR signaling; loss of GPR179 in a mouse model of night blindness prevents targeting of RGS7 complex to the postsynaptic compartment of retinal bipolar neurons. Co-immunoprecipitation, subcellular fractionation, mouse KO model, electroretinography, immunofluorescence The Journal of cell biology High 22689652
2012 RGS7 and RGS11 are the key GTPase-activating proteins in the mGluR6 pathway of retinal rod ON bipolar cells; concurrent elimination of both RGS7 and RGS11 severely reduces the magnitude and dramatically slows onset of light-evoked responses, consistent with persistently high G protein activity. RGS7/RGS11 single and double knockout mice, electroretinography, single-cell patch-clamp recordings Proceedings of the National Academy of Sciences High 22547806
2013 RGS7/Gbeta5 forms macromolecular complexes with GABAB receptors and GIRK channels in hippocampal CA1 pyramidal neurons; co-expression of RGS7/Gbeta5 markedly accelerates GABAB-GIRK current deactivation kinetics; by immunoelectron microscopy, RGS7/Gbeta5 is enriched around excitatory synapses on dendritic spines in proximity to Girk2 and GABAB1. Co-immunoprecipitation, patch-clamp electrophysiology, immunoelectron microscopy Hippocampus High 23804514
2014 RGS7, in cooperation with R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons; deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics; R7BP sets the dynamic range of GIRK responses; RGS7 loss leads to decreased neuronal excitability and deficits in inhibitory synaptic plasticity, learning, and memory. RGS7 knockout mice, whole-cell patch-clamp electrophysiology in hippocampal slices, behavioral testing (learning/memory) eLife High 24755289
2014 Gbeta5-RGS7 suppresses M3R-stimulated Ca2+ release from intracellular stores but also independently enhances Ca2+ influx via a nifedipine-sensitive channel; the enhanced Ca2+ influx effect is independent of RGS7 GTPase-accelerating protein activity and involves a Gq-mediated pathway. Ca2+ imaging with selective channel blockers (nifedipine, 2-APB), pertussis toxin, RGS domain-deficient mutant, Gq inhibitor UBO-QIC Molecular pharmacology High 24586057
2015 GPR158 is essential for RGS7 expression and membrane localization in the brain (GPR158 KO causes post-transcriptional destabilization of RGS7); the RGS7-binding site maps to the C terminus of GPR158 with homology to R7BP; the proximal GPR158 C terminus enhances RGS7 GAP activity by an allosteric mechanism; the distal GPR158 C terminus contains PDE E-gamma-like motifs that selectively recruit activated G proteins. GPR158 knockout mice, Western blot/fractionation, in vitro GTPase assay, domain mutagenesis, co-immunoprecipitation The Journal of biological chemistry High 25792749
2016 RGS7 can form homo-oligomers in mouse brain and transfected cells; self-association requires the DEP domain but not the RGS or DHEX domains; R7BP strongly inhibits RGS7 homo-oligomerization; constitutively active Galphao prevents RGS7-RGS7 interaction; GPR158 can bind the RGS7 homo-oligomer without causing its dissociation. In situ chemical cross-linking, mass spectrometry, co-immunoprecipitation of differentially tagged RGS7, KO mouse tissue The Journal of biological chemistry High 26895961
2016 RGS7/Gbeta5/R7BP complexes localize to the extrasynaptic plasma membrane of dendritic shafts and spines of cerebellar Purkinje cells; R7BP deletion in mice reduces targeting of both RGS7 and Gbeta5 to the plasma membrane in cerebellum. Co-immunoprecipitation, immunohistochemistry, immunoelectron microscopy, R7BP KO mouse model Frontiers in neuroanatomy High 27965545
2018 Crystal structure of the RGS7-Gbeta5-R7BP complex reveals unique organizational features including long-range conformational changes during allosteric modulation; intermolecular interfaces act in synergy for coordinated modulation of GAP activity. X-ray crystallography, molecular dynamics simulation, hydrogen-deuterium exchange mass spectrometry eLife High 30540250
2018 Hippocampal RGS7 forms two distinct complexes with alternative subunit configurations bound to either R7BP or GPR158; both complexes target nearly the entire pool of RGS7 to the plasma membrane; only R7BP-containing complexes (not GPR158-containing complexes) accelerate GIRK and CaV2 channel kinetics modulated by GABABRs; GPR158 overexpression inhibits RGS7-assisted temporal modulation. Quantitative biochemistry (co-IP, fractionation), patch-clamp electrophysiology in cultured neurons and brain slices, genetic KO and overexpression in mice The Journal of neuroscience High 30315127
2018 Chronic stress promotes membrane recruitment of RGS7 via GPR158 in the medial prefrontal cortex; the resultant GPR158-RGS7 complex suppresses homeostatic cAMP regulation by inhibitory GPCRs; RGS7 loss in mice induces antidepressant-like phenotype; restoration of RGS7 within mPFC rescues the phenotype in a GPR158-dependent manner. Mouse KO and viral RGS7 re-expression, biochemical fractionation, cAMP measurement, behavioral assays Neuropsychopharmacology High 30546127
2019 The RGS domains of RGS6 and RGS7 alone are sufficient for Galphao vs. Galphai1 selectivity; three 'disruptor residues' in the RGS6/7 domains non-specifically attenuate RGS-Galpha interactions, while a unique 'modulatory' residue bypasses this inhibitory effect specifically toward Galphao, constituting a two-tier selectivity mechanism. In vitro GTPase assay, site-directed mutagenesis of RGS domain residues, computational structural modeling Journal of molecular biology High 31153905
2019 The GPR158-RGS7 complex controls A-type potassium channel (Kv4.2) function in L2/3 pyramidal neurons of the PFC; GPR158 physically associates with Kv4.2 and promotes its function by suppressing inhibitory cAMP-PKA-mediated phosphorylation; deletion of GPR158 or RGS7 enhances excitability of these neurons and prevents stress-induced decreases in excitability. Co-immunoprecipitation (GPR158-Kv4.2), KO mouse models, patch-clamp electrophysiology, cAMP/PKA pathway pharmacology The Journal of biological chemistry High 31311860
2021 Arginyltransferase (Ate1) facilitates proteasomal degradation of RGS7; deletion of Ate1 in the nervous system raises RGS7 levels in retinal ON bipolar cells and increases light-evoked response sensitivities; RGS7 degradation via proteasome is abolished in Ate1 knockout mouse embryonic fibroblasts. Conditional Ate1 KO mouse, electroretinography, proteasome inhibition assay in MEF cells, Western blot Scientific reports High 33931669
2021 Cryo-EM structure of human GPR158 alone and bound to RGS7-Gbeta5 reveals: GPR158 dimerizes through PAS-fold extracellular and transmembrane domains stabilized by phospholipids; the DHEX domain of RGS7 docks to ICL2, ICL3, TM3 and first coiled-coil helix of GPR158; a second RGS7 molecule is recruited by the second coiled-coil helix; unique features of the RGS7-binding site underlie selectivity of GPR158 for RGS7. Single-particle cryo-EM structure determination Science / Nature communications High 34793198 34815401
2022 RGS7 forms a complex with CaMKII in ventricular cardiomyocytes, supported by key residues K412 and P391 in the RGS domain; RGS7 facilitates CaMKII oxidation, phosphorylation, and CaMKII-dependent oxidative stress and apoptosis following chemotherapy; cardiac-specific RGS7 knockdown protects against doxorubicin cardiotoxicity; RGS7 also drives neuregulin-1 secretion mediating paracrine VCM-EC communication. Co-immunoprecipitation (RGS7-CaMKII), site-directed mutagenesis (K412, P391), cardiac-specific KD/OE in mice, CaMKII oxidation/phosphorylation assays, ROS measurement Proceedings of the National Academy of Sciences High 36574707
2022 In the liver, RGS7 forms a complex with transcription factor ATF3 and histone acetyltransferase Tip60; this complex drives TNFα release from hepatocytes and stellate cells; removal of domains necessary for ATF3/Tip60 binding abolishes RGS7-dependent ROS generation and cell death; hepatic RGS7 knockdown protects against NAFLD-associated fibrosis and inflammation. Co-immunoprecipitation (RGS7-ATF3-Tip60), domain deletion mutagenesis, hepatic RGS7 KD in mice (shRNA), high-fat diet model, TNFα ELISA Antioxidants & redox signaling High 35521658
2023 RGS7 forms a complex with acetyltransferase Tip60 and deacetylase SIRT1 in ventricular cardiomyocytes; this complex controls acetylation of the p65 subunit of NF-kB, driving pro-inflammatory signaling; Tip60 inhibition or SIRT1 activation mitigates RGS7-driven cardiac inflammation. Co-immunoprecipitation (RGS7-Tip60-SIRT1), acetylation status assay of p65, Tip60 inhibitor/SIRT1 activator treatment, cardiac RGS7 OE in mice Cellular and molecular life sciences High 37589751
2012 RGS7 concentrates at the plasma membrane of cell bodies, along processes in lamellipodia/filopodia-like structures, and at dendritic tips in retinal and dorsal root ganglion neurons; at the plasma membrane, RGS7 co-localizes with R7BP, Galphao, and Galphaq; punctate cytoplasmic localization is mediated by the DEP/DHEX domains; centrosomal localization is mediated by the DHEX domain. Immunofluorescence confocal microscopy of native neurons and transfected cell lines, domain deletion analysis Journal of neurochemistry Medium 22640015

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Interaction between RGS7 and polycystin. Proceedings of the National Academy of Sciences of the United States of America 143 10339594
2000 Complexes of the G protein subunit gbeta 5 with the regulators of G protein signaling RGS7 and RGS9. Characterization in native tissues and in transfected cells. The Journal of biological chemistry 131 10840031
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 126 12531899
1998 Identification of the Gbeta5-RGS7 protein complex in the retina. Biochemical and biophysical research communications 116 9731233
2005 Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family. The Journal of cell biology 114 15897264
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
2012 GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes. The Journal of cell biology 88 22689652
2004 RGS-7 completes a receptor-independent heterotrimeric G protein cycle to asymmetrically regulate mitotic spindle positioning in C. elegans. Cell 87 15479638
1999 Gbeta5 prevents the RGS7-Galphao interaction through binding to a distinct Ggamma-like domain found in RGS7 and other RGS proteins. Proceedings of the National Academy of Sciences of the United States of America 87 10051672
2000 Rapid kinetics of regulator of G-protein signaling (RGS)-mediated Galphai and Galphao deactivation. Galpha specificity of RGS4 AND RGS7. The Journal of biological chemistry 83 10942773
1999 RGS7 and RGS8 differentially accelerate G protein-mediated modulation of K+ currents. The Journal of biological chemistry 74 10092682
2014 RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling. eLife 70 24755289
2012 Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proceedings of the National Academy of Sciences of the United States of America 69 22547806
2000 RGS7 is palmitoylated and exists as biochemically distinct forms. Journal of neurochemistry 67 11032900
1999 Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function. Nature medicine 66 10426315
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
2003 Differentially regulated expression of endogenous RGS4 and RGS7. The Journal of biological chemistry 61 14604980
2006 R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism. The Journal of biological chemistry 60 16867977
2008 R9AP and R7BP: traffic cops for the RGS7 family in phototransduction and neuronal GPCR signaling. Trends in pharmacological sciences 59 19042037
2015 Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain. The Journal of biological chemistry 52 25792749
1998 RGS7 attenuates signal transduction through the G(alpha q) family of heterotrimeric G proteins in mammalian cells. Journal of neurochemistry 52 9572280
2021 Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex. Science (New York, N.Y.) 49 34793198
2002 Expression of RGS2, RGS4 and RGS7 in the developing postnatal brain. The European journal of neuroscience 48 11906535
2013 Association of Rgs7/Gβ5 complexes with Girk channels and GABAB receptors in hippocampal CA1 pyramidal neurons. Hippocampus 43 23804514
2008 Targeting of RGS7/Gbeta5 to the dendritic tips of ON-bipolar cells is independent of its association with membrane anchor R7BP. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 18842904
2009 R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38 20043004
2008 Chronic cold exposure increases RGS7 expression and decreases alpha(2)-autoreceptor-mediated inhibition of noradrenergic locus coeruleus neurons. The European journal of neuroscience 36 18461718
2009 The Gbeta5-RGS7 complex selectively inhibits muscarinic M3 receptor signaling via the interaction between the third intracellular loop of the receptor and the DEP domain of RGS7. Biochemistry 35 19182865
2003 G beta 5.RGS7 inhibits G alpha q-mediated signaling via a direct protein-protein interaction. The Journal of biological chemistry 35 12670932
2021 Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5. Nature communications 34 34815401
2014 Differential effects of the Gβ5-RGS7 complex on muscarinic M3 receptor-induced Ca2+ influx and release. Molecular pharmacology 32 24586057
2009 RGS7 and -11 complexes accelerate the ON-bipolar cell light response. Investigative ophthalmology & visual science 32 19797214
1999 Immunohistochemical distribution of RGS7 protein and cellular selectivity in colocalizing with Galphaq proteins in the adult rat brain. Journal of neurochemistry 30 9886068
2007 Intramolecular interaction between the DEP domain of RGS7 and the Gbeta5 subunit. Biochemistry 29 17511476
2011 Gi/o signaling and the palmitoyltransferase DHHC2 regulate palmitate cycling and shuttling of RGS7 family-binding protein. The Journal of biological chemistry 28 21343290
2004 Palmitoylation and plasma membrane targeting of RGS7 are promoted by alpha o. Molecular pharmacology 28 15496508
2000 RGS7 complex formation and colocalization with the Gbeta5 subunit in the adult rat brain and influence on Gbeta5gamma2-mediated PLCbeta signaling. Journal of neuroscience research 26 10723068
2018 Homeostatic cAMP regulation by the RGS7 complex controls depression-related behaviors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 25 30546127
2019 The signaling proteins GPR158 and RGS7 modulate excitability of L2/3 pyramidal neurons and control A-type potassium channel in the prelimbic cortex. The Journal of biological chemistry 22 31311860
2018 Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex. eLife 21 30540250
2023 Non-Ceruloplasmin Copper Identifies a Subtype of Alzheimer's Disease (CuAD): Characterization of the Cognitive Profile and Case of a CuAD Patient Carrying an RGS7 Stop-Loss Variant. International journal of molecular sciences 18 37047347
2018 Inhibitory Signaling to Ion Channels in Hippocampal Neurons Is Differentially Regulated by Alternative Macromolecular Complexes of RGS7. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 30315127
2002 Spinal cord injury induces expression of RGS7 in microglia/macrophages in rats. The European journal of neuroscience 18 11886441
2018 RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells. Scientific reports 17 29330521
2010 Molecular organization of the complex between the muscarinic M3 receptor and the regulator of G protein signaling, Gbeta(5)-RGS7. Biochemistry 17 20443543
2008 Association analysis of Rgs7 variants with panic disorder. Journal of neural transmission (Vienna, Austria : 1996) 17 18762858
2022 A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity. Proceedings of the National Academy of Sciences of the United States of America 16 36574707
2012 Subcellular localization of regulator of G protein signaling RGS7 complex in neurons and transfected cells. Journal of neurochemistry 15 22640015
1998 dRGS7 encodes a Drosophila homolog of EGL-10 and vertebrate RGS7. DNA and cell biology 12 9839808
2022 RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα. Antioxidants & redox signaling 11 35521658
2006 Ischemia-induced increase in RGS7 mRNA expression in gerbil hippocampus. Neuroscience letters 11 16698180
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
2021 Striatal RGS7 Regulates Depression-Related Behaviors and Stress-Induced Reinstatement of Cocaine Conditioned Place Preference. eNeuro 9 33402347
2021 Arginyltransferase (Ate1) regulates the RGS7 protein level and the sensitivity of light-evoked ON-bipolar responses. Scientific reports 9 33931669
2016 Regulator of G Protein Signaling 7 (RGS7) Can Exist in a Homo-oligomeric Form That Is Regulated by Gαo and R7-binding Protein. The Journal of biological chemistry 9 26895961
2016 Cellular and Subcellular Localization of the RGS7/Gβ5/R7BP Complex in the Cerebellar Cortex. Frontiers in neuroanatomy 9 27965545
2023 RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation. Cellular and molecular life sciences : CMLS 7 37589751
2015 Helix 8 and the i3 loop of the muscarinic M3 receptor are crucial sites for its regulation by the Gβ5-RGS7 complex. Biochemistry 5 25551629
2023 Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 37440271
2022 The interaction, mechanism and function of GPR158-RGS7 cross-talk. Progress in molecular biology and translational science 3 36357076
2018 A High-Throughput Time-Resolved Fluorescence Energy Transfer Assay to Screen for Modulators of RGS7/Gβ5/R7BP Complex. Assay and drug development technologies 3 29658790
2015 Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval. Endocrine-related cancer 3 26113603
2023 RGS7 silence protects palmitic acid-induced pancreatic β-cell injury by inactivating the chemokine signaling pathway. Autoimmunity 2 36999276
2025 Silencing RGS7 attenuates atrial fibrillation progression by activating the cGMP-PKG signaling pathway. Biochimica et biophysica acta. Molecular basis of disease 1 40086518
2021 Identification of Potential Modulators of the RGS7/Gβ5/R7BP Complex. SLAS discovery : advancing life sciences R & D 1 34112017
2025 Molecular Mechanism of Dexmedetomidine in Alzheimer's Disease: Machine Learning Identifies RGS7 as a Key Therapeutic Targe. Chemical biology & drug design 0 41169112