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regulator of G-protein signaling 9

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Target not currently curated in GtoImmuPdb

Target id: 2817

Nomenclature: regulator of G-protein signaling 9

Abbreviated Name: RGS9

Family: R7 family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 674 17q24.1 RGS9 regulator of G protein signaling 9
Mouse - 675 11 71.86 cM Rgs9 regulator of G-protein signaling 9
Rat - 677 10q32.1 Rgs9 regulator of G-protein signaling 9
Gene and Protein Information Comments
A splice variant of the mouse RGS9 gene has been reported. This shorter isoform (isoform 2, 484 amino acids; NM_001165934) accelerates termination of the photoresponse in retina [33], whilst the longest isoform, isoform 1 (675 amino acids; NM_011268 ) accelerates Gi/o protein signaling termination in striatal neurons.
Previous and Unofficial Names Click here for help
Database Links Click here for help
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins Click here for help
G Proteins
Name References
Gαi/0 19,28
Interacting Proteins
Name Effect References
Gβ5 Proteolytic stabilization. 26,36,40
Regulator of G-protein signaling 9-binding protein (R9AP) Proteolytic stabilization, subcellular targeting. 21
Regulator of G-protein signaling 7-binding protein (R7BP) Proteolytic stabilization, subcellular targeting. 11,27
Adenylyl cyclase 5 Adenylyl cyclase activity regulation. 41
heat shock 70kDa protein (hsp70) Targeting to degradation. 31
PhLP1 (phosducin-like protein, PDCL) Complex assembly. 20
μ receptor μ receptor and 14-3-3 protein interactions regulate cell signaling. 13,32
β-arrestin Regulation of receptor desensitization. 32
α-actinin-2, NMDA NR1 subunit Regulation of NMDA receptor function. 3
Spinophilin, GRK2 Regulate μ-opioid receptor signaling. 6
Guanylyl cyclase Inhibit guanylyl cyclase. 35
D2 receptor Targeting to the detergent-resistant fraction. 5
Tissue Distribution Click here for help
Retina, striatum.
Species:  Human
Technique:  Northern blot and immunohistochemistry.
References:  43
Rod and cone photoreceptors.
Species:  Mouse
Technique:  Immunohistochemistry.
References:  9,18
Nucleus accumbens, caudoputamen, olfactory tubercle, hypothalamus.
Species:  Mouse
Technique:  In situ hybridisation.
References:  16
Striatum, hypothalamic nuclei.
Species:  Rat
Technique:  In situ hybridisation.
References:  39
Functional Assays Click here for help
Receptor driven modulation of Ca2+ channels.
Species:  Rat
Tissue:  Striatum.
Response measured:  Enhanced basal Ca2+ channel currents and reduced D2 dopamine receptor modulation of Cav2.2 channels.
References:  4
RGS9-2 inhibits Gβγ mediated sensitizaiton of adenylyl cyclases 5 activity.
Species:  Mouse
Tissue:  Striatum and reconstituted HEK293 cells.
Response measured:  Inhibition of receptor stimulated adenylyl cyclase 5 activity.
References:  41
Facilitation of Gβγ reassociation with Gα following antagonizing GPCR activity.
Species:  Human
Tissue:  Transfected cells.
Response measured:  Reassociation of heterotrimer following termination of GPCR signaling.
References:  28
Facilitaiton of GIRK channel deactivation following terminaiton of GPCR signaling.
Species:  None
Tissue:  Protein expression in Xenopus oocytes (using rat and mouse protein co-expression).
Response measured:  Modulaiton of GIRK channel activity.
References:  22
Speeds up the rate of GTP hydrolysis by Gai, Go, Gt in purified recombinant system.
Species:  None
Tissue:  In vitro assays with recombinant proteins.
Response measured:  Acceleration of GTP hydrolysis rate by Ga subunits.
References:  10,19
Physiological Consequences of Altering Gene Expression Click here for help
Mice with RGS9 knockout have delayed termination of photoreceptor response.
Species:  Mouse
Tissue:  Retina.
Technique:  Gene knockout.
References:  7,25
Mice with overexpression of RGS9-1 in rods results in accelerated photoresponse inactivation.
Species:  Mouse
Tissue:  Retina.
Technique:  Gene over-expression.
References:  24
RGS9 knockout mice had increased sensitivity to cocaine, amphetamine, and morphine as evidenced by an enhanced response to psychostimulants.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene knockout.
References:  32,34,42
Down regulation of RGS9-2 enhances antinociceptive effect of morphine as evidenced by an increased morphine antinociceptive effect and delayed tolerance.
Species:  Mouse
Tissue:  Straitum.
Technique:  Antisense/siRNA.
References:  12
RGS9 knockout mice have faster development of tardive dyskinesia in resposne to suppression of dopaminergic signaling.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene knockout.
References:  23
RGS9 knockout mice have deficit in motor coordination and working memory.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene knockout.
References:  1
RGS9 overexpressing mice have a reduced response to cocaine.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene over-expression.
References:  34
Overexpression of RGS9-2 in a monkey Parkinson's disease model showed diminished L-DOPA induced dyskinesia symptoms.
Species:  Monkey
Tissue:  Striatum.
Technique:  Gene over-expression.
References:  15
RGS9 in nucleus accumbens modulates responses to morphine.
Species:  Mouse
Tissue:  Nucleus accumbens.
Technique:  Gene over-expression.
References:  14
RGS9-2 modulates sensory and mood related symptoms of neuropathic pain.
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene knockout.
References:  38
Depletion of RGS9-2 mimics the D2 receptor loss of DYT1 dystonia striatum; RGS9-2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons.
Species:  Mouse
Technique:  SiRNA-mediated gene knockdown; viral overexpression.
References:  2
Gene knockout inhibits NMDAR activity, indicating that RGS7 potentiates NMDAR function in striatal synapses, via a mechanism that involves inhibition of endocannabinoid (AEA) release leading to increased synaptic release of glutamate.
Species:  Mouse
Tissue:  Striatal neurons.
References:  37
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Bradyopsia
Description: Bradyopsia is characterised by a prolonged electroretinal response suppression (PERRS) and stationary subnormal visual acuity and photophobia.
Synonyms: PERRS
prolonged electroretinal response suppression
OMIM: 608415
References:  17,29-30
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Human
Description:  A missense mutation in the catalytic RGS domain of RGS9 is associated with bradyopsia.
Amino acid change:  W299R
Nucleotide change:  T>C
References:  8,17,30
Type:  Truncation
Species:  Human
Description:  Expression of a truncated RGS9 protein is associated with bradyopsia.
Amino acid change:  R128X
References:  17


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1. Blundell J, Hoang CV, Potts B, Gold SJ, Powell CM. (2008) Motor coordination deficits in mice lacking RGS9. Brain Res, 1190: 78-85. [PMID:18073128]

2. Bonsi P, Ponterio G, Vanni V, Tassone A, Sciamanna G, Migliarini S, Martella G, Meringolo M, Dehay B, Doudnikoff E et al.. (2019) RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO Mol Med, 11 (1): e9283. DOI: 0.15252/emmm.201809283 [PMID:30552094]

3. Bouhamdan M, Yan HD, Yan XH, Bannon MJ, Andrade R. (2006) Brain-specific regulator of G-protein signaling 9-2 selectively interacts with alpha-actinin-2 to regulate calcium-dependent inactivation of NMDA receptors. J Neurosci, 26 (9): 2522-30. [PMID:16510730]

4. Cabrera-Vera TM, Hernandez S, Earls LR, Medkova M, Sundgren-Andersson AK, Surmeier DJ, Hamm HE. (2004) RGS9-2 modulates D2 dopamine receptor-mediated Ca2+ channel inhibition in rat striatal cholinergic interneurons. Proc Natl Acad Sci USA, 101 (46): 16339-44. [PMID:15534226]

5. Celver J, Sharma M, Kovoor A. (2012) D(2)-Dopamine receptors target regulator of G protein signaling 9-2 to detergent-resistant membrane fractions. J Neurochem, 120 (1): 56-69. [PMID:22035199]

6. Charlton JJ, Allen PB, Psifogeorgou K, Chakravarty S, Gomes I, Neve RL, Devi LA, Greengard P, Nestler EJ, Zachariou V. (2008) Multiple actions of spinophilin regulate mu opioid receptor function. Neuron, 58 (2): 238-47. [PMID:18439408]

7. Chen CK, Burns ME, He W, Wensel TG, Baylor DA, Simon MI. (2000) Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1. Nature, 403 (6769): 557-60. [PMID:10676965]

8. Cheng JY, Luu CD, Yong VH, Mathur R, Aung T, Vithana EN. (2007) Bradyopsia in an Asian man. Arch Ophthalmol, 125 (8): 1138-40. [PMID:17698770]

9. Cowan CW, Fariss RN, Sokal I, Palczewski K, Wensel TG. (1998) High expression levels in cones of RGS9, the predominant GTPase accelerating protein of rods. Proc Natl Acad Sci USA, 95 (9): 5351-6. [PMID:9560279]

10. Cowan CW, Wensel TG, Arshavsky VY. (2000) Enzymology of GTPase acceleration in phototransduction. Meth Enzymol, 315: 524-38. [PMID:10736724]

11. Drenan RM, Doupnik CA, Boyle MP, Muglia LJ, Huettner JE, Linder ME, Blumer KJ. (2005) Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family. J Cell Biol, 169 (4): 623-33. [PMID:15897264]

12. Garzón J, Rodríguez-Díaz M, López-Fando A, Sánchez-Blázquez P. (2001) RGS9 proteins facilitate acute tolerance to mu-opioid effects. Eur J Neurosci, 13 (4): 801-11. [PMID:11207815]

13. Garzón J, Rodríguez-Muñoz M, López-Fando A, Sánchez-Blázquez P. (2005) Activation of mu-opioid receptors transfers control of Galpha subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization. J Biol Chem, 280 (10): 8951-60. [PMID:15632124]

14. Gaspari S, Papachatzaki MM, Koo JW, Carr FB, Tsimpanouli ME, Stergiou E, Bagot RC, Ferguson D, Mouzon E, Chakravarty S et al.. (2014) Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine. Neuropsychopharmacology, 39 (8): 1968-77. [PMID:24561386]

15. Gold SJ, Hoang CV, Potts BW, Porras G, Pioli E, Kim KW, Nadjar A, Qin C, LaHoste GJ, Li Q et al.. (2007) RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease. J Neurosci, 27 (52): 14338-48. [PMID:18160641]

16. Gold SJ, Ni YG, Dohlman HG, Nestler EJ. (1997) Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. J Neurosci, 17 (20): 8024-37. [PMID:9315921]

17. Hartong DT, Pott JW, Kooijman AC. (2007) Six patients with bradyopsia (slow vision): clinical features and course of the disease. Ophthalmology, 114 (12): 2323-31. [PMID:17826834]

18. He W, Cowan CW, Wensel TG. (1998) RGS9, a GTPase accelerator for phototransduction. Neuron, 20 (1): 95-102. [PMID:9459445]

19. Hooks SB, Waldo GL, Corbitt J, Bodor ET, Krumins AM, Harden TK. (2003) RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity. J Biol Chem, 278 (12): 10087-93. [PMID:12531899]

20. Howlett AC, Gray AJ, Hunter JM, Willardson BM. (2009) Role of molecular chaperones in G protein beta5/regulator of G protein signaling dimer assembly and G protein betagamma dimer specificity. J Biol Chem, 284 (24): 16386-99. [PMID:19376773]

21. Hu G, Wensel TG. (2002) R9AP, a membrane anchor for the photoreceptor GTPase accelerating protein, RGS9-1. Proc Natl Acad Sci USA, 99 (15): 9755-60. [PMID:12119397]

22. Kovoor A, Chen CK, He W, Wensel TG, Simon MI, Lester HA. (2000) Co-expression of Gbeta5 enhances the function of two Ggamma subunit-like domain-containing regulators of G protein signaling proteins. J Biol Chem, 275 (5): 3397-402. [PMID:10652332]

23. Kovoor A, Seyffarth P, Ebert J, Barghshoon S, Chen CK, Schwarz S, Axelrod JD, Cheyette BN, Simon MI, Lester HA et al.. (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. J Neurosci, 25 (8): 2157-65. [PMID:15728856]

24. Krispel CM, Chen D, Melling N, Chen YJ, Martemyanov KA, Quillinan N, Arshavsky VY, Wensel TG, Chen CK, Burns ME. (2006) RGS expression rate-limits recovery of rod photoresponses. Neuron, 51 (4): 409-16. [PMID:16908407]

25. Lyubarsky AL, Naarendorp F, Zhang X, Wensel T, Simon MI, Pugh Jr EN. (2001) RGS9-1 is required for normal inactivation of mouse cone phototransduction. Mol Vis, 7: 71-8. [PMID:11262419]

26. Makino ER, Handy JW, Li T, Arshavsky VY. (1999) The GTPase activating factor for transducin in rod photoreceptors is the complex between RGS9 and type 5 G protein beta subunit. Proc Natl Acad Sci USA, 96 (5): 1947-52. [PMID:10051575]

27. Martemyanov KA, Yoo PJ, Skiba NP, Arshavsky VY. (2005) R7BP, a novel neuronal protein interacting with RGS proteins of the R7 family. J Biol Chem, 280 (7): 5133-6. [PMID:15632198]

28. Masuho I, Xie K, Martemyanov KA. (2013) Macromolecular composition dictates receptor and G protein selectivity of regulator of G protein signaling (RGS) 7 and 9-2 protein complexes in living cells. J Biol Chem, 288 (35): 25129-42. [PMID:23857581]

29. Michaelides M, Li Z, Rana NA, Richardson EC, Hykin PG, Moore AT, Holder GE, Webster AR. (2010) Novel mutations and electrophysiologic findings in RGS9- and R9AP-associated retinal dysfunction (Bradyopsia). Ophthalmology, 117 (1): 120-127.e1. [PMID:19818506]

30. Nishiguchi KM, Sandberg MA, Kooijman AC, Martemyanov KA, Pott JW, Hagstrom SA, Arshavsky VY, Berson EL, Dryja TP. (2004) Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Nature, 427 (6969): 75-8. [PMID:14702087]

31. Posokhova E, Uversky V, Martemyanov KA. (2010) Proteomic identification of Hsc70 as a mediator of RGS9-2 degradation by in vivo interactome analysis. J Proteome Res, 9 (3): 1510-21. [PMID:20095651]

32. Psifogeorgou K, Papakosta P, Russo SJ, Neve RL, Kardassis D, Gold SJ, Zachariou V. (2007) RGS9-2 is a negative modulator of mu-opioid receptor function. J Neurochem, 103 (2): 617-25. [PMID:17725581]

33. Rahman Z, Gold SJ, Potenza MN, Cowan CW, Ni YG, He W, Wensel TG, Nestler EJ. (1999) Cloning and characterization of RGS9-2: a striatal-enriched alternatively spliced product of the RGS9 gene. J Neurosci, 19 (6): 2016-26. [PMID:10066255]

34. Rahman Z, Schwarz J, Gold SJ, Zachariou V, Wein MN, Choi KH, Kovoor A, Chen CK, DiLeone RJ, Schwarz SC et al.. (2003) RGS9 modulates dopamine signaling in the basal ganglia. Neuron, 38 (6): 941-52. [PMID:12818179]

35. Seno K, Kishigami A, Ihara S, Maeda T, Bondarenko VA, Nishizawa Y, Usukura J, Yamazaki A, Hayashi F. (1998) A possible role of RGS9 in phototransduction. A bridge between the cGMP-phosphodiesterase system and the guanylyl cyclase system. J Biol Chem, 273 (35): 22169-72. [PMID:9712827]

36. Snow BE, Krumins AM, Brothers GM, Lee SF, Wall MA, Chung S, Mangion J, Arya S, Gilman AG, Siderovski DP. (1998) A G protein gamma subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gbeta5 subunits. Proc Natl Acad Sci USA, 95 (22): 13307-12. [PMID:9789084]

37. Song C, Anderson GR, Sutton LP, Dao M, Martemyanov KA. (2018) Selective Role of RGS9-2 in Regulating Retrograde Synaptic Signaling of Indirect Pathway Medium Spiny Neurons in Dorsal Striatum. J Neurosci, 38 (32): 7120-7131. [PMID:30006367]

38. Terzi D, Gaspari S, Manouras L, Descalzi G, Mitsi V, Zachariou V. (2014) RGS9-2 modulates sensory and mood related symptoms of neuropathic pain. Neurobiol Learn Mem, 115: 43-8. [PMID:25150149]

39. Thomas EA, Danielson PE, Sutcliffe JG. (1998) RGS9: a regulator of G-protein signalling with specific expression in rat and mouse striatum. J Neurosci Res, 52 (1): 118-24. [PMID:9556034]

40. Witherow DS, Wang Q, Levay K, Cabrera JL, Chen J, Willars GB, Slepak VZ. (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. J Biol Chem, 275 (32): 24872-80. [PMID:10840031]

41. Xie K, Masuho I, Brand C, Dessauer CW, Martemyanov KA. (2012) The complex of G protein regulator RGS9-2 and Gβ(5) controls sensitization and signaling kinetics of type 5 adenylyl cyclase in the striatum. Sci Signal, 5 (239): ra63. [PMID:22932702]

42. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, Neve RL, Sim-Selley LJ, Selley DE, Gold SJ et al.. (2003) Essential role for RGS9 in opiate action. Proc Natl Acad Sci USA, 100 (23): 13656-61. [PMID:14595021]

43. Zhang K, Howes KA, He W, Bronson JD, Pettenati MJ, Chen C, Palczewski K, Wensel TG, Baehr W. (1999) Structure, alternative splicing, and expression of the human RGS9 gene. Gene, 240 (1): 23-34. [PMID:10564809]


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