Affinage

RGS9

Regulator of G-protein signaling 9 · UniProt O75916

Length
674 aa
Mass
77.0 kDa
Annotated
2026-04-28
94 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS9 encodes two tissue-specific splice isoforms—RGS9-1 in photoreceptors and RGS9-2 in striatal neurons—that function as GTPase-accelerating proteins (GAPs) for Gα subunits within obligate heterodimeric complexes with Gβ5, thereby terminating G-protein signaling cascades critical for vision, dopaminergic neurotransmission, and opioid responsiveness (PMID:9459445, PMID:10051575, PMID:12818179, PMID:14595021). In photoreceptors, the RGS9-1·Gβ5L complex is anchored to disk membranes by R9AP via the DEP domain, which enhances catalytic activity up to ~70-fold and is required for proteolytic stability; PDE6γ further potentiates GAP activity toward transducin, and loss-of-function mutations in RGS9 or R9AP cause bradyopsia in humans (PMID:12006596, PMID:14625292, PMID:14702087). In striatal neurons, R7BP palmitoylation targets RGS9-2·Gβ5 to postsynaptic densities where it selectively terminates D2 dopamine and mu-opioid receptor signaling, directly suppresses type 5 adenylyl cyclase activity, and modulates NMDAR-dependent retrograde endocannabinoid signaling in D2-MSNs (PMID:16574655, PMID:22932702, PMID:30006367). RGS9-2 additionally controls D2 receptor surface levels by competing with β-arrestin2 for receptor-associated interactions, preventing lysosomal D2R degradation, while its own stability is governed by R7BP shielding from Hsc70-mediated lysosomal cysteine protease degradation (PMID:30552094, PMID:18094251, PMID:20095651).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Identification of RGS9 as the photoreceptor GAP for transducin resolved the long-standing question of what accelerates GTP hydrolysis on Gαt during photoresponse recovery, with PDE6γ acting as a co-factor.

    Evidence In vitro GTPase assay with purified RGS9 domain, mRNA expression in rod outer segments

    PMID:9459445

    Open questions at the time
    • Physiological requirement not yet shown in vivo
    • Mechanism of PDE6γ potentiation structurally unresolved
    • No information on non-retinal isoforms
  2. 1999 High

    Discovery that RGS9 exists as an obligate heterodimer with Gβ5L (via the GGL domain) and that a brain-specific isoform RGS9-2 modulates mu-opioid receptor signaling established RGS9 as a multi-isoform, multi-tissue GPCR regulator.

    Evidence Co-purification from native photoreceptors, cloning of RGS9-2 from forebrain cDNA, in vitro mu-opioid receptor functional assay

    PMID:10051575 PMID:10066255

    Open questions at the time
    • In vivo requirement for Gβ5 not yet demonstrated
    • Mechanism of isoform-specific substrate selectivity unclear
    • Striatal function of RGS9-2 not yet tested in vivo
  3. 2000 High

    RGS9-1 knockout mice proved that the RGS9-1·Gβ5L complex is essential in vivo for rapid photoresponse recovery and that Gβ5L protein stability depends entirely on RGS9-1 co-expression.

    Evidence Knockout mouse with single-cell electrophysiology and rod outer segment GTPase assay

    PMID:10676965

    Open questions at the time
    • Anchoring mechanism to disk membranes unknown
    • Contribution to cone recovery not yet quantified
    • Regulatory mechanisms (phosphorylation, translocation) not addressed
  4. 2001 High

    Identification of light- and Ca²⁺-dependent phosphorylation at Ser475 (by PKC) and Ser427/428 (by PKA) that reduces GAP activity established a feedback regulatory mechanism linking phototransduction to RGS9-1 catalytic output.

    Evidence Mass spectrometry phosphosite identification, site-directed mutagenesis, recombinant kinase assays, dark/light-adapted retinal comparison

    PMID:11292825 PMID:11601986

    Open questions at the time
    • Physiological impact of phosphorylation on photoresponse kinetics not tested in vivo
    • Phosphatase identity not fully confirmed in situ
    • Whether phosphorylation affects R9AP binding not yet known
  5. 2002 High

    Discovery of R9AP as a transmembrane anchor that binds the DEP domain of RGS9-1 and enhances catalytic activity ~70-fold resolved how RGS9 is targeted to disk membranes and why membrane association is required for full GAP function.

    Evidence Co-immunoprecipitation, DEP domain binding assays, reconstitution on R9AP-containing membranes with GTPase kinetics

    PMID:12006596 PMID:12119397

    Open questions at the time
    • R9AP role in protein stability not yet demonstrated
    • Structural basis of R9AP-mediated catalytic potentiation unresolved
    • Whether an analogous anchor exists for RGS9-2 in brain unknown
  6. 2002 High

    PKCα/θ-mediated Ser475 phosphorylation was shown to reduce RGS9-1 affinity for R9AP and is reversed by PP2A, linking the phosphorylation feedback to the membrane-anchoring mechanism.

    Evidence Kinase purification, recombinant PKC isoform assay, phosphatase assay, R9AP affinity measurement

    PMID:12499365

    Open questions at the time
    • In vivo consequence of PKC phosphorylation on R9AP binding not tested
    • Whether translocation from membranes occurs upon phosphorylation unknown
  7. 2003 High

    RGS9-2 was established as a critical regulator of dopaminergic and opioid signaling in striatum: knockout mice showed enhanced cocaine reward and locomotor responses, enhanced morphine analgesia and tolerance, and dyskinesia upon D2 activation after dopamine depletion.

    Evidence Knockout mouse behavioral assays across cocaine, morphine, and L-DOPA paradigms; viral overexpression in nucleus accumbens; Xenopus oocyte electrophysiology

    PMID:12818179 PMID:14595021 PMID:15728856

    Open questions at the time
    • Cell-type specificity of RGS9-2 action (D1- vs D2-MSN) not resolved
    • Downstream signaling effectors in striatum not identified
    • Whether RGS9-2 acts via GAP activity alone or additional mechanisms unknown
  8. 2003 High

    R9AP knockout demonstrated that R9AP is absolutely required for RGS9 protein stability (not transcription) in vivo, confirming all three proteins (RGS9, Gβ5, R9AP) as obligate subunits of the photoreceptor GAP complex.

    Evidence R9AP knockout mouse with protein vs. mRNA analysis and electrophysiology

    PMID:14625292

    Open questions at the time
    • Mechanism of proteolytic degradation in absence of R9AP not identified
    • Whether R9AP controls RGS9 trafficking beyond stability unclear
  9. 2004 High

    Human loss-of-function mutations in RGS9 (and R9AP) were shown to cause bradyopsia, establishing the first Mendelian disease caused by disruption of the photoreceptor GAP complex.

    Evidence Human genetic sequencing, clinical electrophysiology in affected families

    PMID:14702087

    Open questions at the time
    • Genotype-phenotype correlation across mutation types not established
    • Whether heterozygous carriers have subclinical phenotypes unknown
  10. 2006 High

    R7BP was identified as the brain-specific membrane anchor for RGS9-2, controlling both its subcellular targeting to postsynaptic densities (via palmitoylation and a polybasic motif) and proteolytic stability by shielding it from constitutive degradation.

    Evidence Co-expression studies, degradation kinetics, mutagenesis of R7BP C-terminus, lentiviral knockdown in native striatal neurons, subcellular fractionation

    PMID:16574655 PMID:17158100

    Open questions at the time
    • Identity of the protease pathway not yet determined
    • Whether R7BP also modulates RGS9-2 catalytic activity (as R9AP does for RGS9-1) untested
  11. 2007 High

    The constitutive degradation pathway for RGS9-2 was identified as lysosomal cysteine protease-dependent, with R7BP binding shielding degradation determinants; Hsc70 was later shown to mediate RGS9-2 delivery to the degradation pathway upon R7BP dissociation.

    Evidence Protease inhibitor studies, co-expression with R7BP, quantitative proteomics with knockout controls

    PMID:18094251 PMID:20095651

    Open questions at the time
    • Specific cysteine protease identity not determined
    • Whether Hsc70 delivers RGS9-2 via chaperone-mediated autophagy not confirmed
  12. 2008 High

    The 1.95 Å crystal structure of the Gβ5–RGS9 complex revealed how the canonical RGS domain is integrated within a multidomain scaffold poised for coordinated G-protein regulation.

    Evidence X-ray crystallography

    PMID:18204463

    Open questions at the time
    • Structure of the full tripartite complex with R9AP or R7BP not determined
    • Structural basis of PDE6γ potentiation unresolved
  13. 2012 High

    RGS9-2·Gβ5 was shown to directly suppress basal type 5 adenylyl cyclase activity and attenuate Gβγ stimulation of AC5, revealing a GAP-independent effector-level mechanism for cAMP regulation in striatal neurons.

    Evidence Co-immunoprecipitation, AC5 activity assay, RGS9 knockout mice with cAMP measurements

    PMID:22932702

    Open questions at the time
    • Whether direct AC5 suppression requires Gβ5 or is RGS9-2-autonomous unclear
    • Structural basis of AC5 interaction not determined
  14. 2018 High

    RGS9-2 ablation in D2-MSNs was shown to reduce NMDAR calcium influx and inhibit retrograde endocannabinoid signaling, revealing a role for RGS9-2 in synaptic plasticity at a specific cell-type level.

    Evidence Electrophysiology in identified D1- vs D2-MSNs, calcium imaging, pharmacological dissection

    PMID:30006367

    Open questions at the time
    • Which Gα subunit mediates the NMDAR–endocannabinoid link not identified
    • Whether this mechanism operates in non-striatal neurons unknown
  15. 2019 High

    RGS9-2 was found to stabilize D2 receptor surface expression by competing with β-arrestin2, preventing D2R lysosomal degradation; this mechanism is disrupted in DYT1 dystonia and rescuable by RGS9-2 overexpression.

    Evidence Co-immunoprecipitation, lentiviral overexpression/knockdown, lysosomal inhibitor experiments, electrophysiology in Dyt1 striatal neurons

    PMID:30552094

    Open questions at the time
    • Structural basis of RGS9-2/β-arrestin2 competition at D2R unknown
    • Whether this receptor-stabilizing role extends to other GPCRs untested
    • Therapeutic potential of RGS9-2 in dystonia not validated in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of R9AP/R7BP-mediated catalytic potentiation, whether RGS9-2 nuclear translocation has a defined transcriptional function, the identity of specific cysteine proteases degrading RGS9-2, and how agonist-selective Gα complex formation (e.g., morphine-specific Gαi3 vs. Gαq) translates to distinct signaling outcomes.
  • No structure of the full RGS9·Gβ5·R9AP or R7BP tripartite complex
  • Nuclear function of RGS9-2 rests on reporter assay in a single study
  • Agonist-biased Gα complex formation mechanism unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0003924 GTPase activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-112316 Neuronal System 4 R-HSA-9709957 Sensory Perception 4
Partners
ADCY5ARRB2GNAI1GNAT1GNB5HSPA8RGS9BPRSBP
Complex memberships
RGS9-1·Gβ5L·R9APRGS9-2·Gβ5·R7BP

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RGS9 was identified as the GTPase-accelerating protein (GAP) for the visual G protein transducin (Gαt) in rod outer segments; its RGS domain accelerates GTP hydrolysis by Gαt, and this activity is enhanced by the PDEγ subunit of cGMP phosphodiesterase. In vitro GTPase assay, mRNA expression analysis, protein colocalization to photoreceptor outer segments Neuron High 9459445
1998 RGS9 directly interacts with retinal guanylyl cyclase (retGC) and inhibits its activity, suggesting RGS9 mediates a direct link between the cGMP-phosphodiesterase and guanylyl cyclase systems in phototransduction. 2D gel electrophoresis, antibody binding assay, immunoprecipitation, in vitro GC activity assay, peptide sequencing The Journal of biological chemistry Medium 9712827
1999 Functionally active RGS9 in vertebrate photoreceptors exists as a tight complex with the long splice variant of Gβ5 (Gβ5L); this complex forms when RGS9 and Gβ5L are co-expressed in cell culture, and the GGL domain of RGS9 mediates the Gβ5 interaction. Co-purification from native photoreceptors, co-expression in cell culture, biochemical characterization Proceedings of the National Academy of Sciences of the United States of America High 10051575
1999 RGS9-2, a striatum-specific splice isoform of RGS9 with a unique 191-amino-acid C-terminal extension, dampens Gi/o-coupled mu-opioid receptor response in vitro, while the retinal isoform RGS9-1 does not. Cloning from forebrain cDNA library, in vitro functional assay with mu-opioid receptor, immunohistochemistry The Journal of neuroscience : the official journal of the Society for Neuroscience High 10066255
1999 The PDEγ C-terminal domain (residues 63–87) potentiates RGS9 GAP activity toward Gαt; chimeric RGS9/RGS16 analysis mapped the structural determinants to the α3–α5 region of the RGS9 domain, which faces the PDEγ binding site on Gαt. In vitro GTPase assay, chimeric protein mutagenesis, structure-function analysis Biochemistry High 10213594
2000 RGS9-1 knockout mice lack functional Gβ5L protein (despite normal mRNA) and exhibit severely slowed GTP hydrolysis in rod outer segment membranes and dramatically prolonged photoresponse recovery, establishing RGS9-1/Gβ5L as essential for transducin GTPase acceleration in vivo. Mouse knockout, ROS GTPase assay, electrophysiology (single-cell recordings), Western blot Nature High 10676965
2000 Gβ5L stabilizes RGS9-1 protein and is required for its folding and GAP activity; the GGL-Gβ5 complex modulates GAP activity in response to PDEγ; the C-terminal domain of RGS9-1 contributes to effector stimulation. Native Gβ5 and R7-family RGS proteins exist exclusively as obligate heterodimers in cells, maintained by mutual protein stabilization (non-transcriptional mechanism). In vitro reconstitution, domain deletion mutagenesis, transgenic Xenopus, co-purification, immunoprecipitation The Journal of biological chemistry High 10840031 10978345
2001 RGS9-1 is phosphorylated by an endogenous protein kinase at Ser475 in rod outer segments in a light- and Ca2+-dependent manner; phosphorylation at this site reduces RGS9-1 GAP activity, identified as a potential mechanism for light-adaptation feedback on phototransduction. 32P-ATP labeling, mass spectrometry, site-directed mutagenesis (S475A), in vitro kinase assay, immunoblot of dark- vs. light-adapted retina The Journal of biological chemistry High 11292825
2001 PKA is the major kinase responsible for RGS9-1 phosphorylation in rod outer segments; phosphorylation sites mapped to Ser427 and Ser428; phosphomimetic substitution (Ser→Glu) reduces GAP activity. Kinase inhibitor panel, dibutyryl-cAMP stimulation, recombinant PKA phosphorylation, mutagenesis, in vitro GAP assay Biochemistry High 11601986
2001 RGS9-1 is required for normal inactivation of both rod and cone phototransduction; cones of RGS9-1−/− mice show ~60-fold slower recovery after bright conditioning flash. ERG in knockout mice, immunohistochemistry Molecular vision High 11262419
2001 The C-terminal domain of RGS9-1 (absent in RGS9-2) is critical for tight membrane binding to rod outer segment disk membranes; Gβ5L does not itself play an important role in membrane attachment. Limited proteolysis, recombinant domain constructs, membrane binding assays The Journal of biological chemistry High 11677233
2001 Gβ5 and R7-family RGS proteins (including RGS9) always co-exist as obligate heterodimers in native tissue; Gβ5 co-expression dramatically increases RGS protein levels via protein stabilization, not transcriptional effects. Immunoprecipitation, conventional chromatography, co-expression in COS-7 cells, Western blot The Journal of biological chemistry High 10840031
2001 Noncatalytic domains of RGS9-1·Gβ5 play a decisive role in establishing substrate specificity for transducin bound to its effector (PDE) rather than free transducin; double L353E/R360P mutation reversed specificity of the catalytic domain alone but not of the full complex. Site-directed mutagenesis, single-turnover GTPase assay The Journal of biological chemistry High 11495924
2002 R9AP (RGS9-1 Anchor Protein) is a 25-kDa transmembrane phosphoprotein that binds to the N-terminal domain of RGS9-1 via its DEP domain and anchors RGS9-1·Gβ5 to photoreceptor disk membranes via a C-terminal transmembrane helix; R9AP is expressed exclusively in photoreceptors. Co-immunoprecipitation from detergent extracts, cDNA cloning, immunohistochemistry, domain binding assays Proceedings of the National Academy of Sciences of the United States of America High 12119397
2002 Specific binding of RGS9-1·Gβ5L to R9AP-containing photoreceptor membranes (via the DEP domain) produces an ~70-fold increase in RGS9-1 catalytic activity toward transducin GTPase; membrane association is DEP-domain dependent. Urea extraction, recombinant protein binding to native membranes, in vitro GTPase assay, domain deletion constructs The Journal of biological chemistry High 12006596
2002 Light exposure triggers translocation of the RGS9-1·Gβ5L complex (along with transducin) to detergent-resistant membrane rafts; this translocation requires Gαt activation (blocked by GTPγS or pertussis toxin, mimicked by AlF4−); phosphorylation of RGS9-1 occurs exclusively within rafts. Detergent-resistant membrane fractionation, light/dark adaptation experiments, pharmacological manipulation of G-protein state Current biology : CB Medium 11882295
2002 PKCα and PKCθ are the major kinases responsible for RGS9-1 phosphorylation at Ser475 in rod outer segments; phosphorylation is removed by protein phosphatase 2A; PKC-mediated phosphorylation reduces RGS9-1 affinity for R9AP. Kinase purification, in vitro kinase assay with recombinant PKC isoforms, synthetic peptide substrate, protein phosphatase assay, affinity assay The Journal of biological chemistry High 12499365
2002 The N-terminus of RGS9-1 directly inhibits retinal guanylyl cyclase (retGC) activity; the GGL and RGS domains serve as internal suppressors of this inhibitory activity; direct interaction of retGC with RGS9-1 N-terminus confirmed by immunoprecipitation and overlay. Immunoprecipitation, overlay assay, in vitro retGC activity assay with RGS9-1 fragments Biochemical and biophysical research communications Medium 11485301
2003 RGS9-2 modulates dopamine D2 receptor function in striatum; viral overexpression of RGS9-2 in nucleus accumbens reduced locomotor responses to cocaine and D2 agonists; RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine; in Xenopus oocytes, RGS9-2 accelerated off-kinetics of D2R-induced GIRK currents. Viral-mediated overexpression, knockout mouse behavioral assays, Xenopus oocyte electrophysiology (GIRK currents) Neuron High 12818179
2003 R9AP knockout results in complete absence of RGS9 protein (not mRNA) from retina, establishing that R9AP determines the proteolytic stability of the RGS9·Gβ5 complex; all three proteins (RGS9, Gβ5, R9AP) are obligate members of the photoreceptor GAP complex. R9AP knockout mouse, Western blot, mRNA analysis, electrophysiology The Journal of biological chemistry High 14625292
2003 The DEP domain of RGS9 is essential for its delivery to rod outer segments; transgenic mice expressing DEP-domain-deleted RGS9 show normal expression levels but complete exclusion from outer segments; the DEP domain mediates interaction with R9AP which both targets RGS9 to outer segments and potentiates its catalytic activity. Transgenic mouse (DEP-deleted RGS9), quantitative serial tangential sectioning-Western blot, electrophysiology, domain interaction assays The Journal of neuroscience : the official journal of the Society for Neuroscience High 14614075
2003 Gbeta5/RGS9 and other Gbeta5/R7 dimers are selective GAPs for Gi-family Gα subunits (not Gαq or Gα11); Gbeta5/RGS9 and Gbeta5/RGS11 are more potent GAPs for Gαi1, Gαi2, and Gαi3 than Gbeta5/RGS6 or Gbeta5/RGS7. Purified Sf9-expressed proteins, steady-state GTPase assay in proteoliposomes with M1/M2 muscarinic receptors The Journal of biological chemistry High 12531899
2003 RGS9-2 via its DEP domain colocalizes with D2 dopamine receptors in mammalian cells; RGS9-2 DEP domain preferentially accelerates termination of D2 receptor (not M2 muscarinic) signals in oocytes; RGS9 knockout mice develop abnormal involuntary movements when D2 signaling is activated after dopaminergic inhibition, and RGS9-2 deletion abnormally inhibits glutamate-elicited currents in striatal neurons. Colocalization in transfected mammalian cells, oocyte electrophysiology, mouse knockout, striatal neuron recordings, behavioral analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 15728856
2003 RGS9 (as RGS9-2) is essential for normal opiate action; mice lacking RGS9 show enhanced responses to acute and chronic morphine; acute morphine increases RGS9-2 in NAc while chronic exposure decreases it, showing reciprocal regulation. Knockout mouse behavioral assays (analgesia, reward, dependence/withdrawal), Western blot Proceedings of the National Academy of Sciences of the United States of America High 14595021
2003 R9AP binding site on RGS9-1 is in the N-terminal (DEP-containing) domain; R9AP reconstituted into lipid vesicles increases RGS9-1 GAP activity 4-fold; the DEP domain is required for high-affinity binding (Kd <10 nM) to R9AP vesicles. Recombinant protein purification, lipid vesicle reconstitution, binding affinity measurements, single-turnover GTPase assay The Journal of biological chemistry High 12560335
2004 Mutations in RGS9 or R9AP in humans cause bradyopsia (delayed photoreceptor deactivation with difficulty adapting to luminance changes); R9AP enhances RGS9 activity up to 70-fold and anchors it to photoreceptor membranes. Human genetic analysis (sequencing), clinical electrophysiology, phenotype characterization Nature High 14702087
2004 RGS9-2 specifically modulates D2 dopamine receptor (not M2 muscarinic receptor) inhibition of Cav2.2 calcium channels in striatal cholinergic interneurons; dialysis with RGS9 constructs enhanced basal Ca2+ channel currents; the DEP-GGL domain antagonizes endogenous RGS9-2 activity. Whole-cell patch clamp in striatal neurons, intracellular dialysis with RGS9 constructs, in vitro GTPase assay Proceedings of the National Academy of Sciences of the United States of America High 15534226
2004 The brain-specific unique polyproline-rich C-terminus of RGS9-2 contains sequences sufficient to target RGS9-2 to the nucleus of COS-7 cells and striatal neurons; Gβ5 further enhances nuclear localization of RGS9-2 (but not RGS9-1); nuclear RGS9-2 increases transcriptional activity of a neuronal gene construct. Immunocytochemistry, immunoblot fractionation, deletion construct transfection, reporter gene assay Biochimica et biophysica acta Medium 15110994
2005 Mu-opioid receptor (MOR) activation promotes transfer of Gα subunits from MOR to RGS9-2 complexes, followed by Ser phosphorylation of RGS9-2 and its association with 14-3-3 proteins; tolerance-inducing morphine doses stabilize Gα retention by RGS9-2; knockdown of RGS9-2 prevents this transfer and blocks tolerance. Co-immunoprecipitation from periaqueductal gray membranes, in vivo antisense knockdown, [35S]GTPγS binding, GTPase assay The Journal of biological chemistry Medium 15632124
2006 R7BP controls the proteolytic stability of RGS9-2: co-expression with R7BP dramatically elevates RGS9-2 and Gβ5 protein levels by reducing constitutive proteolysis; R7BP binds RGS9 via an interface formed by the DEP domain paired with the R7H domain; lentiviral R7BP knockdown in native striatal neurons reduces RGS9-2 protein. Co-expression in cells, protein degradation kinetics, site-directed mutagenesis of binding interface, lentiviral RNAi in striatal neurons, Western blot The Journal of biological chemistry High 17158100
2006 Subcellular targeting of RGS9-2 to plasma membrane and postsynaptic densities in striatal neurons requires the C-terminal 21 amino acids of R7BP, specifically the synergistic action of a polybasic motif and palmitoylated cysteines; depalmitoylation of R7BP unmasks nuclear localization sequences enabling nuclear import. Subcellular fractionation, site-directed mutagenesis of R7BP C-terminus, live-cell imaging, postsynaptic density fractionation The Journal of biological chemistry High 16574655
2006 R9AP potentiation of RGS9-1 GAP activity is a direct increase in catalytic activity (not simply enhanced G-protein binding); the N-terminal trihelical domain of R9AP contains the RGS9-1 binding site, but the entire R9AP molecule is required for potentiation. Kinetic GTPase assay, R9AP domain deletion constructs, binding assays Biochemistry High 16939221
2007 RGS9-2 constitutive degradation is mediated by lysosomal cysteine proteases; R7BP binding to RGS9-2 shields degradation determinants and controls RGS9-2 expression at the posttranslational level; R7BP also targets RGS9-2 to postsynaptic densities in neurons. Protease inhibitor studies, co-expression with R7BP, Western blot quantification, immunohistochemistry in developing striatum The Journal of neuroscience : the official journal of the Society for Neuroscience High 18094251
2007 Striatal RGS9-2 overexpression (via viral vector) in MPTP-lesioned monkeys and 6-OHDA-lesioned rats reduces L-DOPA-induced involuntary movements without reducing anti-parkinsonian effects of L-DOPA; RGS9 knockout mice are more susceptible to L-DOPA-induced dyskinesia, establishing RGS9-2 as a negative modulator of dyskinesia. Viral vector overexpression in primates and rats, RGS9 knockout mice, behavioral scoring The Journal of neuroscience : the official journal of the Society for Neuroscience High 18160641
2008 Crystal structure of the Gβ5-RGS9 complex at 1.95 Å resolution reveals a canonical RGS domain functionally integrated within a molecular complex poised for coordination of multiple G-protein activation and deactivation steps. X-ray crystallography Nature structural & molecular biology High 18204463
2008 RGS9-2 can functionally replace RGS9-1 in rod photoreceptors and supports normal photoresponse recovery; RGS9-2 inactivates transducin regardless of its effector interactions (G protein-effector complex-independent), whereas RGS9-1 preferentially acts on the G protein–effector complex. Transgenic mouse replacement of RGS9-1 with RGS9-2, single-cell electrophysiology, ERG Proceedings of the National Academy of Sciences of the United States of America High 19098104
2010 RGS9-2 inhibits dopamine-mediated internalization of D2R specifically (not delta opioid receptor); this requires the DEP domain and GTPase-accelerating activity of RGS9-2; RGS4 does not share this specificity. Transfection of RGS9-2 and mutants in cells, receptor internalization assay, receptor-specific comparison Journal of neurochemistry Medium 20477943
2010 Hsc70 is recruited to the intrinsically disordered C-terminal domain of RGS9-2 following its dissociation from R7BP, mediating RGS9-2 degradation; identified by quantitative in vivo interactome analysis using knockout controls. Quantitative proteomics with knockout controls, co-immunoprecipitation, Western blot Journal of proteome research Medium 20095651
2011 Gβ5 is required for RGS9 to associate with membrane anchors (R7BP or R9AP); the binding interface between the N-terminal lobe of RGS9 and Gβ5 interaction surface is needed for R7BP recruitment; distinct molecular determinants in the DEP/DHEY–Gβ5 interface differentially control R7BP binding vs. proteolytic stabilization. Protein-protein interaction assays, co-localization, protein stability assays, site-directed mutagenesis The Journal of biological chemistry High 21511947
2011 β-arrestin2 scaffolds interactions among the DEP domain of RGS9-2, Gβ5, R7BP, and D3R; β-arrestin2 competes with R7BP and Gβ5 to place RGS9-2 in an open cytosolic conformation capable of inhibiting GPCR signaling; receptor affinity for β-arrestin2 determines the selectivity of RGS9-2 for a given receptor. Co-immunoprecipitation, transfection with domain mutants, signaling assays in cells Molecular and cellular biology Medium 22006018
2011 RGS9-2 in striatum forms distinct Gα-containing complexes depending on the MOR agonist: morphine uniquely promotes RGS9-2/Gαi3 association; RGS9-2/Gαq complexes form with multiple MOR agonists but not morphine; repeated morphine forms RGS9-2/Gβ5/Gαq complexes associated with analgesic tolerance. Co-immunoprecipitation from striatum, pharmacological manipulation, behavioral assays The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 21490202
2012 RGS9-2/Gβ5 complex directly interacts with and suppresses basal activity of type 5 adenylyl cyclase (AC5); it also attenuates Gβγ stimulation of AC5 by facilitating Gαo GTPase activity; and accelerates AC5 recovery from Gαi inhibition by increasing Gαi deactivation rate. Mice lacking RGS9 show increased cAMP production and enhanced AC5 sensitization upon opioid withdrawal. Co-immunoprecipitation, AC5 activity assay, RGS9 knockout mice, cAMP measurements Science signaling High 22932702
2013 RGS9-1 and Gβ5L undergo light-dependent translocation from rod inner segments to outer segments; prolonged dark adaptation causes them to accumulate in inner segments while their anchor R9AP remains in outer segments; RGS9-1 is phosphorylated at S475 in the dark, and dim light exposure leads to rapid de-phosphorylation. Immunofluorescence, Western blot with phospho-specific antibody, light/dark adaptation protocol PloS one Medium 23555598
2018 RGS9-2 ablation in D2-MSNs reduces NMDAR-mediated calcium influx, increases AMPAR/NMDAR ratio, and inhibits retrograde endocannabinoid signaling from D2-MSNs to CB1 receptors on presynaptic terminals, leading to increased mEPSC frequency and altered paired-pulse ratio; effects are selective to D2-MSNs, not D1-MSNs. Electrophysiology in identified MSN subtypes, calcium imaging, pharmacological dissection, behavioral assays with MK-801/ketamine The Journal of neuroscience : the official journal of the Society for Neuroscience High 30006367
2019 RGS9-2 in striatum controls D2 receptor protein levels by competing with β-arrestin2 for D2R binding protein interactions, preventing lysosomal degradation of D2R; RGS9-2 depletion mimics D2R loss in DYT1 dystonia, and RGS9-2 overexpression rescues D2R levels and electrophysiological responses in Dyt1 striatal neurons. Western blot, co-immunoprecipitation, lentiviral overexpression, lysosomal inhibitor experiments, electrophysiology EMBO molecular medicine High 30552094

Source papers

Stage 0 corpus · 94 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1. Nature 375 10676965
1998 RGS9, a GTPase accelerator for phototransduction. Neuron 295 9459445
2003 RGS9 modulates dopamine signaling in the basal ganglia. Neuron 215 12818179
2003 Essential role for RGS9 in opiate action. Proceedings of the National Academy of Sciences of the United States of America 203 14595021
1999 The GTPase activating factor for transducin in rod photoreceptors is the complex between RGS9 and type 5 G protein beta subunit. Proceedings of the National Academy of Sciences of the United States of America 185 10051575
2005 D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 144 15728856
1999 Cloning and characterization of RGS9-2: a striatal-enriched alternatively spliced product of the RGS9 gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 135 10066255
2004 Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Nature 133 14702087
2002 R9AP, a membrane anchor for the photoreceptor GTPase accelerating protein, RGS9-1. Proceedings of the National Academy of Sciences of the United States of America 132 12119397
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
2003 The DEP domain determines subcellular targeting of the GTPase activating protein RGS9 in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 99 14614075
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