Affinage

RGS7

Regulator of G-protein signaling 7 · UniProt P49802

Length
495 aa
Mass
57.7 kDa
Annotated
2026-06-10
66 papers in source corpus 42 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS7 is a GTPase-accelerating protein (GAP) that terminates Gi/o-family heterotrimeric G protein signaling by accelerating GTP hydrolysis on Galpha subunits, with intrinsic selectivity for Galphao that resides entirely within its RGS domain (PMID:10942773, PMID:31153905). RGS7 functions obligatorily as a heterodimer with Gbeta5, an interaction conferred by its Ggamma-like (GGL) domain that is both necessary and sufficient for selective Gbeta5 binding; dimerization mutually stabilizes both proteins post-transcriptionally, and the two are essentially undetectable as monomers in native tissue (PMID:9731233, PMID:10051672, PMID:10840031, PMID:10648734). Although the isolated RGS domain acts on Galphao and Galphai, the assembled RGS7-Gbeta5 complex restricts GAP activity toward Gi-family Galpha subunits while also engaging Galphaq-coupled signaling (PMID:11032900, PMID:12531899, PMID:12670932). Because RGS7 is a short-lived protein cleared by the proteasome — degradation facilitated by arginyltransferase Ate1 and antagonized by TNF-alpha/p38 signaling and by polycystin — its abundance and membrane localization are tightly controlled by accessory partners (PMID:10339594, PMID:10426315, PMID:33931669). Two membrane anchors govern its function: palmitoylated R7BP, whose palmitate cycling (catalyzed by DHHC2 and modulated by Gi/o signaling) targets the complex to the plasma membrane and is required for efficient GPCR regulation (PMID:15897264, PMID:16867977, PMID:21343290), and the orphan receptor GPR158 (and retinal GPR179), which both recruit RGS7 to the membrane, allosterically enhance its GAP activity, and post-transcriptionally stabilize RGS7 expression in brain (PMID:22689652, PMID:25792749). Receptor selectivity is encoded by the RGS7 DEP domain, which engages in an intramolecular interaction with Gbeta5 that switches the complex between 'open' and 'closed' states; the DEP domain directly binds the i3 loop and helix 8 of the muscarinic M3 receptor, and this two-site engagement drives the conformational switch underlying selective M3R inhibition (PMID:17511476, PMID:19182865, PMID:20443543, PMID:25551629). Functionally, RGS7-Gbeta5 sets the kinetics of GPCR-gated channels: it is a principal GAP for the retinal mGluR6 ON-bipolar pathway and, with R7BP, accelerates GABAB-receptor-coupled GIRK and CaV2 channel deactivation in hippocampal neurons to control excitability, synaptic plasticity, and learning (PMID:22547806, PMID:23804514, PMID:24755289, PMID:30315127). In the prefrontal cortex the GPR158-RGS7 complex governs cAMP homeostasis and Kv4.2 channel function to mediate stress-induced depressive phenotypes (PMID:30546127, PMID:31311860), and in the striatum RGS7 shapes responses to cocaine (PMID:20043004). Structural work, including a crystal structure of RGS7-Gbeta5-R7BP and cryo-EM of the GPR158-RGS7-Gbeta5 assembly, defines the interfaces and long-range allostery underlying complex assembly and dimeric receptor coupling (PMID:30540250, PMID:34793198, PMID:34815401). Beyond neural GPCR signaling, RGS7 drives pathology in non-neuronal tissues through GAP-independent protein complexes: with CaMKII in cardiomyocytes to promote chemotherapy-induced cardiotoxicity, and with ATF3/Tip60 (and a Tip60/SIRT1-NF-kB axis) in liver and heart to promote inflammation and oxidative stress (PMID:36574707, PMID:35521658, PMID:37589751).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1998 High

    Established that an RGS protein could physically partner with a G-beta subunit, redefining RGS7 as part of a constitutive Gbeta5 complex rather than a free GAP.

    Evidence Native co-purification of Gbeta5 and RGS7 from bovine retina cytosol

    PMID:9731233

    Open questions at the time
    • Did not define the binding domain or functional consequence of the interaction
    • No GAP activity measured
  2. 1999 High

    Mapped Gbeta5 binding to the GGL domain and showed Gbeta5 selectivity is encoded there, while revealing that Gbeta5 binding can block Galphao engagement — framing dimerization as both an assembly and a regulatory event.

    Evidence Recombinant reconstitution, GGL deletion and Ggamma1 domain-swap mutagenesis, plus comparative GGL/Gbeta5 specificity analysis

    PMID:10051672 PMID:10339615

    Open questions at the time
    • Did not establish whether Gbeta5 inhibits or modifies GAP activity in vivo
    • Galpha-subtype GAP kinetics not quantified
  3. 1999 Medium

    Identified RGS7 as a short-lived proteasome substrate whose stability is regulated, establishing protein turnover as a control point for RGS7 levels.

    Evidence Proteasome inhibition and co-IP with polycystin C-terminus; cell-based degradation assays with p38 inhibition and TNF receptor 1 knockout mice

    PMID:10339594 PMID:10426315

    Open questions at the time
    • E3 ligase and degron not identified at this stage
    • Direct phosphorylation sites on RGS7 not confirmed
  4. 1999 Medium

    Defined RGS7 Galpha selectivity (Galphao/i3/z) and showed it modulates GIRK channel gating, linking the GAP to physiological ion channel kinetics.

    Evidence In vitro binding assay and GIRK electrophysiology in Xenopus oocytes

    PMID:10092682

    Open questions at the time
    • Weak deactivation effect left the physiological role ambiguous
    • No Gbeta5 included in the channel assay
  5. 2000 High

    Quantified the RGS domain's intrinsic Galphao-selective GAP activity and demonstrated this specificity is domain-autonomous, decoupling catalysis from N/C-terminal and Gbeta5 context.

    Evidence Stopped-flow GTPase kinetics with GST-RGS domain truncations; reciprocal native co-IP and obligate-dimer purification from brain

    PMID:10648734 PMID:10840031 PMID:10942773

    Open questions at the time
    • Reconciling in vitro Gq inhibition with absence of native Galpha co-purification
    • In vivo substrate identity not resolved
  6. 2000 High

    Showed membrane RGS7 is palmitoylated and that lipidation does not alter intrinsic GAP catalysis, separating membrane targeting from enzymatic function.

    Evidence Metabolic [3H]-palmitate labeling, subcellular fractionation, in vitro GTPase reconstitution from brain extracts

    PMID:11032900

    Open questions at the time
    • Palmitoylation site not yet mapped
    • Enzyme catalyzing palmitoylation unknown
  7. 2003 High

    Established in defined proteoliposomes that Gbeta5/RGS7 acts as a GAP on Gi-family Galpha within receptor-coupled systems, and that it can interact with Galphaq in living cells, broadening its functional Galpha range.

    Evidence Purified-protein proteoliposome GTPase assays; FRET and co-IP in mammalian cells

    PMID:12531899 PMID:12670932

    Open questions at the time
    • Lower potency versus other R7 RGS proteins left its preferred substrate uncertain
    • Cellular Gq versus Gi/o substrate preference unresolved
  8. 2004 High

    Connected Galphao activation to RGS7 membrane recruitment/palmitoylation and mapped the C133 palmitoylation site and DEP-domain requirement, defining a feedback loop where the G protein controls GAP localization.

    Evidence Palmitate labeling, fractionation and site-directed mutagenesis in HEK293; recombinant GAP assay with cortical localization and genetic epistasis in C. elegans

    PMID:15479638 PMID:15496508

    Open questions at the time
    • The palmitoyltransferase acting on RGS7 C133 not identified
    • Whether the C. elegans receptor-independent role generalizes to mammals unclear
  9. 2005 High

    Identified R7BP as a palmitoylation-regulated membrane anchor that markedly enhances RGS7 regulation of GIRK signaling, establishing a dedicated trafficking adaptor.

    Evidence Co-IP, live-cell imaging, palmitate labeling and GIRK electrophysiology; follow-up mutagenesis of the R7BP polybasic motif

    PMID:15897264 PMID:16867977

    Open questions at the time
    • Enzyme controlling R7BP palmitate cycling not identified at this stage
    • Functional meaning of nuclear translocation unclear
  10. 2007 Medium

    Defined an intramolecular DEP-Gbeta5 interaction creating open/closed conformations disrupted by R7BP, providing a structural switch that tunes RGS7 activity.

    Evidence GST pull-down, co-IP, FRET, DEP-domain mutagenesis (E73/D74) and Ca2+ mobilization assays

    PMID:17511476

    Open questions at the time
    • Direct structural confirmation of the conformational states pending
    • Physiological trigger for the switch in vivo not established
  11. 2009 High

    Showed the DEP domain confers GPCR selectivity by directly binding the M3R i3 loop, revealing receptor recognition independent of GAP catalysis.

    Evidence Ca2+ mobilization assays, GST pull-down with recombinant i3 loop, deletion mutagenesis of RGS7 and M3R

    PMID:19182865

    Open questions at the time
    • Whether selectivity extends to other Gq receptors not tested broadly
    • Structural basis of i3-loop recognition not resolved
  12. 2009 Medium

    Linked striatal RGS7 to cocaine behavioral responses and revealed R7BP-balanced interplay with RGS9-2, placing RGS7 in dopaminergic GPCR circuits.

    Evidence Striatum-specific viral RGS7 knockdown, locomotor assays, biochemical complex analysis in knockout mice

    PMID:20043004

    Open questions at the time
    • Specific dopamine receptor substrate not identified
    • Direct GAP target in striatum unconfirmed
  13. 2010 Medium

    Resolved M3R inhibition into a two-site mechanism in which the receptor C-terminus drives the open conformation, mechanistically uniting DEP binding and the conformational switch.

    Evidence Mutagenesis of RGS7 and M3R, GST pull-down and Ca2+ mobilization assays; later helix-8 mapping with CD spectroscopy

    PMID:20443543 PMID:25551629

    Open questions at the time
    • Open/closed transition not visualized structurally at the receptor interface
    • Stoichiometry of the receptor-bound complex unknown
  14. 2011 Medium

    Identified DHHC2 as the palmitoyltransferase for R7BP and showed Gi/o signaling stabilizes membrane RGS7 complexes by inhibiting depalmitoylation, closing a signaling-dependent localization loop.

    Evidence DHHC2 siRNA, palmitate labeling, live-cell imaging and pharmacological Gi/o manipulation

    PMID:21343290

    Open questions at the time
    • Depalmitoylating enzyme not identified
    • Direct effect on RGS7 GAP output in neurons not measured
  15. 2012 High

    Identified GPR158/GPR179 as receptor anchors that recruit and augment RGS7 complexes, and established RGS7/RGS11 as the principal GAPs of the retinal mGluR6 ON-bipolar pathway.

    Evidence Co-IP and GPCR signaling assays; GPR179 and RGS7/RGS11 double knockout mice with ERG and single-cell patch-clamp

    PMID:22547806 PMID:22689652

    Open questions at the time
    • Whether GPR158/179 act as classical GPCRs upstream of RGS7 unclear
    • Mechanism of allosteric enhancement not yet mapped
  16. 2014 High

    Demonstrated that RGS7/R7BP controls GABAB-GIRK signaling to set neuronal excitability, synaptic plasticity, and learning, establishing a behaviorally relevant channel-kinetic role.

    Evidence RGS7 knockout mice, patch-clamp, LTP/LTD measurements and behavioral testing; complementary co-IP and immuno-EM at CA1 spines

    PMID:23804514 PMID:24586057 PMID:24755289

    Open questions at the time
    • GAP-independent Ca2+ influx coupling to M3R mechanistically incomplete
    • Relative contribution of R7BP versus other anchors in vivo
  17. 2015 High

    Established GPR158 as essential for brain RGS7 stability and membrane localization and as an allosteric enhancer of its GAP activity, with the receptor C-terminus harboring R7BP-like and G-protein-recruiting motifs.

    Evidence GPR158 knockout mice, fractionation, co-IP, in vitro GAP assay and domain mutagenesis; M3R helix-8 interaction mapping

    PMID:25551629 PMID:25792749

    Open questions at the time
    • Endogenous ligand/activation of GPR158 not defined
    • Mechanism of post-transcriptional RGS7 stabilization unresolved
  18. 2016 Medium

    Showed RGS7 forms DEP-dependent homo-oligomers regulated antagonistically by R7BP and Galphao, adding self-association as a layer of complex assembly control.

    Evidence Chemical cross-linking, mass spectrometry, and differentially tagged co-IP in cells and brain with knockout mice

    PMID:26895961

    Open questions at the time
    • Functional role of homo-oligomers in signaling unclear
    • Physiological stoichiometry in vivo not quantified
  19. 2018 High

    Provided the first crystal structure of RGS7-Gbeta5-R7BP and tied chronic-stress GPR158-RGS7 cAMP control to depressive phenotypes, integrating structure with prefrontal behavioral function.

    Evidence X-ray crystallography with MD and HDX-MS; knockout and viral mPFC rescue with cAMP and behavioral assays; CA1 dual-complex electrophysiology

    PMID:30315127 PMID:30540250 PMID:30546127

    Open questions at the time
    • Structural basis of GPR158 coupling not yet resolved at this stage
    • Direct cAMP-controlling GPCR substrate in mPFC not pinned down
  20. 2019 Medium

    Defined the GPR158-RGS7 control of Kv4.2 via cAMP-PKA suppression and refined the molecular code (disruptor/modulatory residues) for Galphao-selective GAP activity.

    Evidence Co-IP and patch-clamp in GPR158/RGS7 knockout PFC neurons; in vitro GAP assays with chimeric RGS domain mutants

    PMID:31153905 PMID:31311860

    Open questions at the time
    • Whether Kv4.2 regulation requires RGS7 GAP catalysis unclear
    • Link between GAP-residue code and channel phenotype not directly tested
  21. 2021 High

    Determined the cryo-EM structure of dimeric GPR158 bound to RGS7-Gbeta5, defining the intracellular interfaces and dual-RGS7 recruitment platform, and identified Ate1-mediated arginylation as a degradation pathway controlling RGS7 levels in vivo.

    Evidence Single-particle cryo-EM solved independently by two labs; conditional Ate1 knockout mice with ERG and cell-based proteasome assays

    PMID:33931669 PMID:34793198 PMID:34815401

    Open questions at the time
    • How receptor occupancy translates to GAP activation not captured structurally
    • Identity of the E3 ligase downstream of arginylation unknown
  22. 2022 High

    Revealed GAP-independent pathological functions: RGS7-CaMKII complexes drive doxorubicin cardiotoxicity, and RGS7-ATF3/Tip60 complexes promote NAFLD-related hepatic inflammation, extending RGS7 beyond canonical GPCR signaling.

    Evidence Co-IP with mutagenesis, cardiac/hepatic-specific knockdown and overexpression in mice, oxidative-stress/apoptosis assays and inhibitor rescue

    PMID:35521658 PMID:36574707

    Open questions at the time
    • Whether these scaffolding roles require Gbeta5 association is unaddressed
    • How RGS7 is regulated/recruited in non-neuronal tissues unknown
  23. 2023 Medium

    Showed RGS7 controls a Tip60/SIRT1-NF-kB p65 acetylation axis in cardiomyocytes driving paracrine fibroblast activation, defining a transcriptional/inflammatory mode of RGS7 action in heart.

    Evidence Co-IP, Tip60 inhibition, SIRT1 activation, cytokine ELISA, myocardial RGS7 overexpression and fibroblast co-culture

    PMID:37589751

    Open questions at the time
    • Direct demonstration that RGS7 is the catalytic/regulatory determinant of p65 acetylation incomplete
    • Relationship between this axis and canonical GAP function unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous ligands/activation states of the orphan receptor anchors GPR158/GPR179, and how receptor occupancy is transduced into RGS7 GAP modulation, remain undefined.
  • No defined agonist linking receptor anchors to RGS7 activation
  • Mechanism connecting structural coupling to catalytic enhancement unresolved
  • Whether non-neuronal scaffolding roles intersect with canonical GAP function unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-9709957 Sensory Perception 2
Partners
ATF3CAMK2CHRM3GNAO1GNB5GPR158GPR179R7BP
Complex memberships
GPR158-RGS7-Gbeta5 complexRGS7-Gbeta5 heterodimerRGS7-Gbeta5-R7BP complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Gbeta5 and RGS7 form a tight heterodimeric complex in bovine retina cytosolic fraction; this was the first demonstration of an interaction between a G-beta subunit and an RGS protein. Native protein purification from bovine retina, co-purification, biochemical characterization Biochemical and biophysical research communications High 9731233
1999 The GGL (Ggamma-like) domain of RGS7 is necessary and sufficient for selective binding to Gbeta5; deletion of the GGL domain abolishes Gbeta5 binding while retaining Galpha interaction; substitution of the GGL domain with Ggamma1 switches binding specificity from Gbeta5 to Gbeta1. Furthermore, Gbeta5 binding to RGS7 blocks RGS7 interaction with Galphao, indicating Gbeta5 acts as a specific RGS inhibitor. Recombinant protein reconstitution, gel-filtration, cation-exchange chromatography, immunoprecipitation, deletion and domain-swap mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10051672
1999 RGS7 is a short-lived protein that undergoes rapid proteasome-dependent degradation. Interaction with the C-terminal domain of polycystin (PKD1 product) inhibits this degradation and causes relocalization of RGS7 to the membrane. Proteasome inhibitor treatment, co-immunoprecipitation, subcellular localization assays in transfected cells Proceedings of the National Academy of Sciences of the United States of America Medium 10339594
1999 The GGL domains of RGS6, RGS7, and RGS11 selectively interact with Gbeta5 and not other Gbeta subunits; mutation of the conserved Phe-61 in Ggamma2 to tryptophan (the residue present in all GGL domains) increases Gbeta5/Ggamma2 heterodimer stability, highlighting the importance of this position for GGL/Gbeta5 association. Co-expression in cells, co-immunoprecipitation, GGL domain mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10339615
1999 RGS7 recombinant protein preferentially binds Galphao, Galphai3, and Galphaz. When co-expressed with GIRK1/2 in Xenopus oocytes, RGS7 accelerates activation kinetics of GIRK currents but has a significantly weaker effect on deactivation compared to RGS8, indicating differential modulation of G protein-mediated K+ channel gating. In vitro binding assay, electrophysiology in Xenopus oocyte expression system The Journal of biological chemistry Medium 10092682
1999 TNF-alpha prevents proteasome-dependent degradation of RGS7 through 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, abrogated in mice lacking TNF receptor 1. Cell-based proteasome degradation assay, p38 inhibitor treatment, in vivo mouse model with TNF receptor 1 knockout Nature medicine Medium 10426315
2000 Native Gbeta5 and RGS7 from brain co-purify as tight obligatory heterodimers; neither RGS-free Gbeta5 nor Gbeta5-free RGS7 is detectable. Co-expression of Gbeta5 dramatically increases RGS7 protein level and vice versa by a non-transcriptional mechanism based on increased protein stability upon dimerization. Gbeta5-RGS7 dimers inhibit Galphaq-mediated Ca2+ response in transfected cells but do not co-precipitate with Galphao or Galphaq from native tissue. Immunoprecipitation, conventional chromatography from brain, co-expression in COS-7 cells, Ca2+ signaling assay The Journal of biological chemistry High 10840031
2000 RGS7 Gbeta5 complex co-purifies from brain membranes with RGS6 as ~1:1 mixture; Gbeta5 and RGS7 can be reciprocally co-immunoprecipitated from brain; no copurifying Galpha subunits or canonical Ggamma subunits detected, suggesting Gbeta5-RGS7 operates outside canonical Gbetagamma framework. Immunoaffinity purification from brain membrane, MALDI-MS, reciprocal co-immunoprecipitation The Journal of neuroscience High 10648734
2000 RGS7 RGS domain selectively stimulates GTPase activity of Galphao over Galphai1/2 with catalytic efficiencies of 0.44, 0.10, and 0.02 x10^6 M^-1 s^-1 respectively; this Galphao specificity resides within the RGS domain itself and does not require N- or C-terminal extensions or Gbeta5. Stopped-flow spectroscopy measuring intrinsic tryptophan fluorescence decay, GST-fusion RGS domain fragments, kinetic analysis The Journal of biological chemistry High 10942773
2000 Membrane-bound but not cytosolic RGS7 is palmitoylated in brain. Gbeta5 is not palmitoylated. Both palmitoylated and unpalmitoylated forms of RGS7 complexed with Gbeta5 equally stimulate Galphao GTPase activity. The isolated RGS domain of RGS7 selectively activates Galphao and Galphai1 in vitro, while the RGS7/Gbeta5 complex selectively interacts with Galphao only. Metabolic [3H]-palmitate labeling, subcellular fractionation, in vitro GTPase assay, pull-down from brain extracts Journal of neurochemistry High 11032900
2003 Purified Gbeta5/R7 dimers (including Gbeta5/RGS7) stimulate steady-state GTPase activity of Gi-family Galpha subunits (but not Galphaq or Galpha11) in proteoliposomes reconstituted with muscarinic receptor-coupled G-proteins. Gbeta5/RGS7 showed lower potency and maximal GAP activity toward Galphai1/i2/i3 compared to Gbeta5/RGS9 and Gbeta5/RGS11, and inhibited Gbeta5/RGS11-stimulated GTPase activity of Galphao. Sf9 cell-purified recombinant proteins, proteoliposome reconstitution, steady-state GTPase assay The Journal of biological chemistry High 12531899
2003 Gbeta5-RGS7 complex directly interacts with Galphaq in living mammalian cells, as shown by FRET between fluorescent protein-tagged constructs. Gbeta5-RGS7 inhibits Galphaq-mediated Ca2+ signaling in cells. FRET spectroscopy and FRET microscopy in transfected mammalian cells, co-immunoprecipitation The Journal of biological chemistry Medium 12670932
2004 In C. elegans, RGS-7 localizes to the cell cortex and its RGS domain stimulates GTP hydrolysis by Galphao (demonstrated with recombinant proteins). RGS-7 promotes asymmetric spindle positioning by completing a receptor-independent heterotrimeric G protein cycle; genetic epistasis places RGS-7 downstream of the non-receptor G protein activators RIC-8 and GPR-1/2, functioning to asymmetrically enhance rather than simply inactivate G protein signaling. Genetic epistasis in C. elegans, recombinant protein GTPase assay, cortical localization by imaging Cell High 15479638
2004 Alphao promotes plasma membrane localization and palmitoylation of Gbeta5-RGS7. Palmitoylation requires active alphao (constitutively active alphao R179C works; lipidation-deficient alphao G2A and RGS-insensitive alphao G184S do not). Cysteine 133 of RGS7 is a palmitoylation site; C133S mutation and deletion of DEP domain residues 76-128 abolish alphao-mediated membrane recruitment. Subcellular fractionation, [3H]-palmitate metabolic labeling, site-directed mutagenesis, HEK293 cell expression Molecular pharmacology High 15496508
2005 R7BP is a novel neuronal protein that binds R7-Gbeta5 complexes (including RGS7-Gbeta5) and controls their subcellular distribution. R7BP is palmitoylated at its C-terminus, targeting it to the plasma membrane; depalmitoylation translocates the R7BP-R7-Gbeta5 complex from the plasma membrane to the nucleus. Palmitoylated R7BP greatly augments RGS7's ability to attenuate GPCR-mediated GIRK activation compared to non-palmitoylated R7BP. Co-immunoprecipitation, live cell imaging, [3H]-palmitate labeling, electrophysiology (GIRK current measurement) The Journal of cell biology High 15897264
2006 R7BP augments the function of RGS7-Gbeta5 complex exclusively through a palmitoylation-regulated plasma membrane-targeting mechanism; cytoplasmic RGS7-Gbeta5-R7BP heterotrimers and RGS7-Gbeta5 heterodimers are equivalently inefficient at regulating GPCR signaling. A C-terminal polybasic motif of R7BP mediates nuclear localization, palmitoylation, and plasma membrane targeting. Electrophysiology (GIRK channel assay), mutagenesis of R7BP polybasic motif, subcellular localization assays The Journal of biological chemistry Medium 16867977
2007 The DEP domain of RGS7 engages in an intramolecular interaction with the Gbeta5 subunit. Specific residues E73 and D74 of RGS7 DEP domain mediate this interaction; ED/SG mutation that mimics RGS9 diminishes DEP-Gbeta5 binding. R7BP binding disrupts this intramolecular interaction. The complex can exist in 'closed' (DEP-Gbeta5 interacting, less active toward Gq signaling) and 'open' conformations. GST pull-down, co-immunoprecipitation, FRET, mutagenesis, Ca2+ mobilization assay Biochemistry Medium 17511476
2008 RGS7/Gbeta5 complex is specifically targeted to the dendritic tips of retinal ON-bipolar cells. This targeting occurs independently of R7BP, revealing an adapter-independent mechanism for RGS7/Gbeta5 complex delivery to postsynaptic compartments. Immunofluorescence confocal microscopy in R7BP knockout mice, comparison of RGS7 localization with and without R7BP The Journal of neuroscience Medium 18842904
2008 Intracellular administration of RGS7 via patch-clamp electrodes mimics stress-induced decrease in alpha2-autoreceptor-mediated inhibition of locus coeruleus neurons, demonstrating that elevated RGS7 directly attenuates alpha2-autoreceptor/GIRK signaling. Intracellular RGS7 delivery via patch-clamp electrophysiology, single-unit recordings in vivo and in vitro The European journal of neuroscience Medium 18461718
2009 The Gbeta5-RGS7 complex selectively inhibits muscarinic M3 receptor (M3R) signaling but not other Gq-coupled receptors (M1, M5, H1, GNRH receptors). The DEP domain of RGS7 is necessary and sufficient for this selectivity; it directly binds the third intracellular loop (i3 loop) of M3R in vitro. Deletion of a portion of the i3 loop abolishes receptor sensitivity to Gbeta5-RGS7. Ca2+ mobilization assay, GST pull-down with recombinant i3 loop, deletion mutagenesis of RGS7 and M3R Biochemistry High 19182865
2009 RGS7 striatal expression controls locomotor sensitivity to cocaine; striatum-specific knockdown of RGS7 increases cocaine-induced motor stimulation. RGS7 complex formation with R7BP in the striatum is regulated by RGS9-2 expression, establishing an interplay between RGS7 and RGS9-2 balanced by R7BP. Striatum-specific RGS7 knockdown (viral), locomotor behavioral assays, biochemical analysis of complex formation in knockout mice Neuropsychopharmacology Medium 20043004
2010 Gbeta5-RGS7 inhibits M3R signaling through a two-site interaction: (1) the DEP domain binds the i3 loop and (2) the C-terminus of M3R induces the 'open' conformation by causing dissociation of the intramolecular DEP-Gbeta5 interaction. Mutations that stabilize the open state of Gbeta5-RGS7 allow it to inhibit M3R lacking the C-terminal tail. Site-directed mutagenesis of RGS7 and M3R, GST pull-down, Ca2+ mobilization assay Biochemistry Medium 20443543
2011 R7BP palmitate cycling is mediated by the palmitoyltransferase DHHC2; DHHC2 silencing redistributes R7BP (and thus RGS7 complexes) from plasma membrane to nucleus. Gi/o signaling inhibits R7BP depalmitoylation, stabilizing membrane association of R7-Gbeta5 GAP complexes including RGS7-containing complexes. DHHC2 siRNA knockdown, [3H]-palmitate labeling, live cell imaging, pharmacological Gi/o manipulation The Journal of biological chemistry Medium 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 prevents targeting of RGS7 to the postsynaptic compartment of bipolar neurons in the retina, disrupting night vision signaling. Co-immunoprecipitation, cell-based GPCR signaling assays, GPR179 knockout mouse immunohistochemistry, electroretinography The Journal of cell biology High 22689652
2012 RGS7 and RGS11 are the key GAPs for the mGluR6 pathway in retinal rod ON-bipolar cells; concurrent elimination of both dramatically slows and reduces the light-evoked ON-bipolar response. RGS7 alone contributes to setting light response onset kinetics. RGS7/RGS11 double knockout mice, electroretinography, single-cell patch-clamp recordings Proceedings of the National Academy of Sciences of the United States of America High 22547806
2013 Rgs7/Gbeta5 forms macromolecular complexes with GABAB receptors and GIRK channels in hippocampal CA1 pyramidal neurons, shown by co-immunoprecipitation. Co-expression of Rgs7/Gbeta5 markedly accelerates GABAB-GIRK current deactivation kinetics. Immunoelectron microscopy reveals Rgs7 and Gbeta5 are enriched around excitatory synapses on dendritic spines, co-distributing with Girk2 and GABABR1. Co-immunoprecipitation, patch-clamp electrophysiology, immunoelectron microscopy Hippocampus High 23804514
2014 RGS7, in cooperation with R7BP, controls GABABR-GIRK signaling in hippocampal pyramidal neurons. RGS7 deletion dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics, leading to decreased neuronal excitability, disrupted inhibitory synaptic plasticity, and deficits in learning and memory. R7BP sets the dynamic range of GIRK responses. RGS7 knockout mice, patch-clamp electrophysiology, behavioral testing (learning and memory tasks), LTP/LTD measurements eLife High 24755289
2014 Gbeta5-RGS7, independent of its RGS domain GAP activity, couples M3R to a nifedipine-sensitive Ca2+ influx channel. This effect involves a Gq-mediated pathway and is distinct from suppression of Ca2+ release from intracellular stores. Ca2+ imaging, pharmacological dissection with nifedipine, 2-APB, pertussis toxin, Gq inhibitor UBO-QIC, RGS domain-deficient RGS7 mutant Molecular pharmacology Medium 24586057
2015 GPR158 is essential for RGS7 expression and membrane localization in the brain: GPR158 knockout causes post-transcriptional destabilization of RGS7 and loss of membrane association. The C-terminus of GPR158 contains an RGS7-binding site with homology to R7BP. The proximal GPR158 C-terminus allosterically enhances RGS7 GAP activity. The distal GPR158 C-terminus contains phosphodiesterase E-gamma-like motifs that selectively recruit activated G proteins. GPR158 knockout mice, biochemical fractionation, co-immunoprecipitation, in vitro GAP activity assay, domain mutagenesis The Journal of biological chemistry High 25792749
2015 The central portion of M3R i3 loop (aa 304-345) and helix 8 (requiring T553 and L558) are both required for interaction with Gbeta5-RGS7; disruption of helix 8 alpha-helical structure by Pro substitutions abolishes Gbeta5-RGS7 binding to M3R. Deletion and point mutagenesis of M3R, GST pull-down, circular dichroism spectroscopy, Ca2+ mobilization assay, pharmacological chaperone rescue Biochemistry Medium 25551629
2016 RGS7 can form homo-oligomers requiring the DEP domain but not the RGS, DHEX domains or Gbeta5. R7BP strongly inhibits RGS7 homo-oligomerization; constitutively active Galphaо prevents RGS7-RGS7 interaction; GPR158 binds the homo-oligomer without disrupting it. Chemical cross-linking, mass spectrometry, co-immunoprecipitation of differentially tagged RGS7 constructs in transfected cells and brain, knockout mice The Journal of biological chemistry Medium 26895961
2018 Crystal structure of the RGS7-Gbeta5-R7BP complex reveals unique organizational features. Combined with molecular dynamics and mass spectrometry, the structure shows long-range conformational changes and allosteric modulation through intermolecular interfaces during complex assembly. X-ray crystallography, molecular dynamics simulation, hydrogen-deuterium exchange mass spectrometry eLife High 30540250
2018 Chronic stress promotes membrane recruitment of RGS7 via GPR158 in medial prefrontal cortex. The resulting GPR158-RGS7 complex suppresses homeostatic cAMP regulation by inhibitory GPCRs. RGS7 loss induces antidepressant-like phenotype; restoration of RGS7 within mPFC rescues the phenotype in a GPR158-dependent manner. Mouse knockout models, viral RGS7 re-expression in mPFC, biochemical fractionation, cAMP measurements, behavioral assays Neuropsychopharmacology Medium 30546127
2018 In hippocampal CA1 neurons, RGS7 forms two distinct macromolecular complexes: one with R7BP and one with GPR158. Both complexes target RGS7 to the plasma membrane. Only R7BP-containing RGS7 complexes accelerate GIRK and CaV2 channel deactivation kinetics in response to GABABR stimulation; GPR158 overexpression has the opposite effect, inhibiting RGS7-mediated temporal modulation of both channel types. Quantitative co-immunoprecipitation, patch-clamp electrophysiology in cultured neurons and brain slices, knockout mice, viral overexpression The Journal of neuroscience High 30315127
2019 RGS6 and RGS7 achieve selective GAP activity toward Galphao over Galphai1 through a two-tiered mechanism: conserved 'disruptor residues' broadly reduce RGS-Galpha interactions, but a unique 'modulatory residue' specifically rescues activity toward Galphao. Isolated RGS domains are sufficient for this specificity. In vitro GAP assay with purified RGS domain constructs, site-directed mutagenesis, comparative analysis with chimeric RGS domains Journal of molecular biology Medium 31153905
2019 The GPR158-RGS7 complex controls A-type potassium channel (Kv4.2) function in layer 2/3 PFC pyramidal neurons. GPR158 physically associates with Kv4.2 and promotes its function by suppressing inhibitory cAMP-PKA-mediated phosphorylation. Deletion of GPR158 or RGS7 enhances neuronal excitability and prevents stress-induced changes. Co-immunoprecipitation, patch-clamp electrophysiology, GPR158/RGS7 knockout mice, pharmacological PKA manipulation The Journal of biological chemistry Medium 31311860
2021 Cryo-EM structure of human GPR158 alone and in complex with RGS7-Gbeta5 reveals: GPR158 forms a homodimer stabilized by phospholipids with a Cache extracellular domain; the structural basis of GPR158 coupling to RGS7-Gbeta5 involves the ICL2, ICL3, TM3, and first helix of the cytoplasmic coiled-coil providing a platform for the DHEX domain of RGS7, while the second helix recruits a second RGS7 molecule. Single-particle cryo-electron microscopy Science High 34793198 34815401
2021 Arginyltransferase (Ate1) facilitates proteasomal degradation of RGS7; conditional deletion of Ate1 in the nervous system raises RGS7 protein levels in retinal ON-bipolar cells and increases sensitivity of light-evoked responses. In cultured cells, RGS7 proteasomal degradation is abolished in Ate1 knockout cells. Conditional Ate1 knockout mice, electroretinography, western blot, proteasome inhibitor experiments in MEF cells Scientific reports Medium 33931669
2022 In ventricular cardiomyocytes, RGS7 forms a complex with CaMKII supported by key residues K412 and P391 in the RGS domain of RGS7. This RGS7-CaMKII complex facilitates CaMKII oxidation and phosphorylation, driving oxidative stress, mitochondrial dysfunction, and apoptosis following chemotherapy exposure. Cardiac-specific RGS7 knockdown protects against doxorubicin-induced cardiotoxicity; RGS7 overexpression induces fibrosis and cell death reversed by CaMKII inhibition. RGS7 also drives neuregulin-1 release for paracrine endothelial signaling. Co-immunoprecipitation, site-directed mutagenesis (K412, P391), cardiac-specific knockdown, RGS7 overexpression in mice, doxorubicin treatment, CaMKII inhibitor rescue, oxidative stress/apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 36574707
2022 In liver, RGS7 forms a unique complex with transcription factor ATF3 and histone acetyltransferase Tip60. Domains required for ATF3/Tip60 binding are necessary for RGS7-dependent reactive oxygen species generation and cell death. RGS7 drives TNF-alpha release from hepatocytes and stellate cells; RGS7 knockdown reverses steatosis and oxidative stress caused by direct TNFalpha exposure. Co-immunoprecipitation, domain deletion analysis, RGS7 knockdown in mice (high-fat diet model), ROS/cell death assays, cytokine ELISA Antioxidants & redox signaling Medium 35521658
2023 In ventricular cardiomyocytes, RGS7 forms a complex with acetyltransferase Tip60 and deacetylase SIRT1 and controls acetylation of the p65 subunit of NF-kB. RGS7-driven, Tip60/SIRT1-dependent inflammatory cytokines from cardiomyocytes act in paracrine on cardiac fibroblasts to induce transdifferentiation and extracellular matrix remodeling. SIRT1 activation counteracts detrimental RGS7 effects in heart. Co-immunoprecipitation, Tip60 inhibitor, SIRT1 activator, cytokine ELISA, RGS7 overexpression in murine myocardium, fibroblast co-culture Cellular and molecular life sciences Medium 37589751

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 127 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 71 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 44 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
2021 Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5. Nature communications 35 34815401
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
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
2004 Palmitoylation and plasma membrane targeting of RGS7 are promoted by alpha o. Molecular pharmacology 29 15496508
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
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
2015 Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval. Endocrine-related cancer 4 26113603
2023 RGS7 silence protects palmitic acid-induced pancreatic β-cell injury by inactivating the chemokine signaling pathway. Autoimmunity 3 36999276
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
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

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