regulator of G-protein signaling 8 | R4 family | IUPHAR/BPS Guide to PHARMACOLOGY

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regulator of G-protein signaling 8

Target not currently curated in GtoImmuPdb

Target id: 2813

Nomenclature: regulator of G-protein signaling 8

Abbreviated Name: RGS8

Family: R4 family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 180 1q25 RGS8 regulator of G protein signaling 8
Mouse - 180 1 G3 Rgs8 regulator of G-protein signaling 8
Rat - 180 13q21 Rgs8 regulator of G-protein signaling 8
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins
G Proteins
Name References
Gαi/0, Gαq/11 3,6,15,19,21,27,30,32
Interacting Proteins
Name Effect References
M1 receptor 7
PAR1 RGS8 binds to PAR1 in the presence of Gαo and inhibits PAR1/Gαi/o-mediated adenylyl cyclase and ERK activation. 14
Ataxin-2 Regulates RGS8 translation in purkinje cells 4
Spinophilin (SPL) SPL can removee the direct binding of RGS8 from M1 muscurinic acetylcholine receptor (M1-mAChR) and forms the M1-SPL-RGS8 complex and enhances the inhibitory function of RGS8. SPL can also bind to M2, and M3 mAChR and can recruit RGS8 to these receptors. This enhances the regulatory function of RGS8 on the M3-mAChR system, but the acceleration function of RGS8 on the M2-mediated signaling could not be enhanced by SPL. 5,9

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Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CCG-50014 Hs Inhibition 5.0 pIC50 3,32
pIC50 5.0 (IC50 1.1x10-5 M) [3,32]
Description: Inhibition of Gαo binding
RGS4 inhibitor 13 Hs Inhibition 4.4 pIC50 32
pIC50 4.4 (IC50 3.61x10-5 M) [32]
Description: Inhibition of Gαo binding
RGS4 inhibitor 11b Hs Inhibition 4.1 pIC50 32
pIC50 4.1 (IC50 8.35x10-5 M) [32]
Description: Inhibition of Gαo binding
Inhibitor Comments
CCG-500014 inhibits GTPase accelerating activity of RGS8 [3].
RGS inhibitor peptide 1 (Ac-Val-Lys-[Cys-Thr-Gly-Ile-Cys]-Glu-NH2) and peptide 2 inhibits RGS8 activity in rat monocytes [20].
Tissue Distribution
Embryonic endocrine pancreas and mouse models of diabetes.
Species:  Mouse
Technique:  Green fluorescent protein (GFP) visualization and Immunofluorescence staining.
References:  33
Cerebellar Purkinje cell layer, several midbrain nuclei.
Species:  Rat
Technique:  Northen blot, in situ hybridisation
References:  6,23
Dendrites and cell body of cerebellar Purkinje cells.
Species:  Rat
Technique:  Western blot.
References:  8
Developing cerebellar Purkinje cells.
Species:  Rat
Technique:  In situ hybridisation.
References:  26
NK cells.
Species:  Rat
Technique:  RT-PCR
References:  11
Nucleus accumbens.
Species:  Rat
Technique:  RT-PCR
References:  12
Physiological Functions
RGS8 prevents Gαo-induced neurite outgrowth and activation of Necdin protein by inhibiting PAR1/Gαi/o-mediated adenylyl cyclase and ERK activation.
Species:  Human
Tissue:  HEK293 cells
References:  14
RGS8 negatively modulates melanin concentrating hormone receptor 1 (MCH1R)-mediated calcium signaling.
Species:  Human
Tissue:  HEK293T cells.
References:  17-18
RGS8 accelerates the modulation of G-protein-coupled inwardly rectifying K+ channels.
Species:  Rat
Tissue:  Sympathetic neurons, Xenopus oocytes, HEK293 cells.
References:  1-2,8,21-24
RGS8 attenuates the G protein–dependent inhibition of N-type calcium (Ca) channels.
Species:  Human
Tissue:  HEK293 cells.
References:  16
Modulates PAR1 and M3 muscarinic acetylcholine receptor cell surface expression.
Species:  Human
Tissue:  HEK293 cells
References:  13
Expression of RGS8 inhibits the growth arrest response to mating pheromone, slowing G1 arrest and differentiation.
Species:  None
Tissue:  Xenopus oocytes
References:  25
Physiological Consequences of Altering Gene Expression
RGS8 null mutant mice were viable, fertile and showed apparently normal development. Histological analysis in these mice showed no apparent abnormalities in morphology of cerebellar layer or Purkinje cells.
Species:  Mouse
Tissue:  Cerebellar layer, Purkinje cells.
Technique:  Targeting in embryonic stem cells.
References:  10
Knockdown of RGS8 significantly decreased carbachol-mediated calcium mobilization and protease-activated receptor 1 (PAR1)-mediated calcium mobilization.
Species:  Human
Tissue:  HEK293 cells
Technique:  RNA interference (RNAi).
References:  13
Xenobiotics Influencing Gene Expression
Amphetamine (AMPH) administration significantly downregulate Rgs8 mRNA expression.
Species:  Rat
Tissue:  Nucleus accumbens
Technique:  qRT-PCR
References:  29
Broad spectrum DNA methystransferase (DNMT) inhibitor, 5-aza deoxycitidine strongly upregulates RGS8.
Species:  Human
Tissue:  Human neural progenitor cells (hNP), SK-N-BE human neuroblastoma cells.
Technique:  qRT-PCR
References:  31
Clinically-Relevant Mutations and Pathophysiology
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
References:  33
Disease:  Prostate cancer
Disease Ontology: DOID:10283
OMIM: 176807
References:  28
Gene Expression and Pathophysiology Comments
Cancer mutation overview for RGS8 (summary from the TCGA dataset within
40 mutations (2 nonsense) distributed from amino acids 2-163
Arg (R)14 has 3 independent occurrences (R14K/M/S)
4 residues have 2 independent occurrences
there are 29 single occurrence mutations

RGS8 mutaions have been reported in these cancers:
melanoma (>2.5%), non-Hodgkin lymphoma (2%), endometrial (2%), non-small cell lung, colorectal (>1%), pancreatic (<1%), bladder, cervical, esophagogastric, ovarian, and breast

RGS8 deletions have been reported in these cancers:
soft tissue sarcoma (< 1%) and bladder


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1. Benians A, Nobles M, Hosny S, Tinker A. (2005) Regulators of G-protein signaling form a quaternary complex with the agonist, receptor, and G-protein. A novel explanation for the acceleration of signaling activation kinetics. J. Biol. Chem., 280 (14): 13383-94. [PMID:15677457]

2. Benians A, Nobles M, Tinker A. (2004) Participation of RGS8 in the ternary complex of agonist, receptor and G-protein. Biochem. Soc. Trans., 32 (Pt 6): 1045-7. [PMID:15506959]

3. Blazer LL, Zhang H, Casey EM, Husbands SM, Neubig RR. (2011) A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. Biochemistry, 50 (15): 3181-92. [PMID:21329361]

4. Dansithong W, Paul S, Figueroa KP, Rinehart MD, Wiest S, Pflieger LT, Scoles DR, Pulst SM. (2015) Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. PLoS Genet., 11 (4): e1005182. [PMID:25902068]

5. Fujii S, Yamazoe G, Itoh M, Kubo Y, Saitoh O. (2008) Spinophilin inhibits the binding of RGS8 to M1-mAChR but enhances the regulatory function of RGS8. Biochem. Biophys. Res. Commun., 377 (1): 200-4. [PMID:18834863]

6. 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]

7. Itoh M, Nagatomo K, Kubo Y, Saitoh O. (2006) Alternative splicing of RGS8 gene changes the binding property to the M1 muscarinic receptor to confer receptor type-specific Gq regulation. J. Neurochem., 99 (6): 1505-16. [PMID:17064349]

8. Itoh M, Odagiri M, Abe H, Saitoh O. (2001) RGS8 protein is distributed in dendrites and cell body of cerebellar Purkinje cell. Biochem. Biophys. Res. Commun., 287 (1): 223-8. [PMID:11549278]

9. Kurogi M, Nagatomo K, Kubo Y, Saitoh O. (2009) Effects of spinophilin on the function of RGS8 regulating signals from M2 and M3-mAChRs. Neuroreport, 20 (13): 1134-9. [PMID:19609226]

10. Kuwata H, Nakao K, Harada T, Matsuda I, Aiba A. (2008) Generation of RGS8 null mutant mice by Cre/loxP system. Kobe J Med Sci, 53 (6): 275-81. [PMID:18762722]

11. Kveberg L, Ryan JC, Rolstad B, Inngjerdingen M. (2005) Expression of regulator of G protein signalling proteins in natural killer cells, and their modulation by Ly49A and Ly49D. Immunology, 115 (3): 358-65. [PMID:15946253]

12. Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, Scheideler MA, Garnier M. (2004) Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. Brain Res. Mol. Brain Res., 122 (1): 24-34. [PMID:14992813]

13. Laroche G, Giguère PM, Roth BL, Trejo J, Siderovski DP. (2010) RNA interference screen for RGS protein specificity at muscarinic and protease-activated receptors reveals bidirectional modulation of signaling. Am. J. Physiol., Cell Physiol., 299 (3): C654-64. [PMID:20573995]

14. Lee J, Ghil S. (2016) Regulator of G protein signaling 8 inhibits protease-activated receptor 1/Gi/o signaling by forming a distinct G protein-dependent complex in live cells. Cell. Signal., 28 (5): 391-400. [PMID:26829215]

15. Masuho I, Itoh M, Itoh H, Saitoh O. (2004) The mechanism of membrane-translocation of regulator of G-protein signaling (RGS) 8 induced by Galpha expression. J. Neurochem., 88 (1): 161-8. [PMID:14675160]

16. Melliti K, Meza U, Fisher R, Adams B. (1999) Regulators of G protein signaling attenuate the G protein-mediated inhibition of N-type Ca channels. J. Gen. Physiol., 113 (1): 97-110. [PMID:9874691]

17. Miyamoto-Matsubara M, Chung S, Saito Y. (2010) Functional interaction of regulator of G protein signaling-2 with melanin-concentrating hormone receptor 1. Ann. N. Y. Acad. Sci., 1200: 112-9. [PMID:20633139]

18. Miyamoto-Matsubara M, Saitoh O, Maruyama K, Aizaki Y, Saito Y. (2008) Regulation of melanin-concentrating hormone receptor 1 signaling by RGS8 with the receptor third intracellular loop. Cell. Signal., 20 (11): 2084-94. [PMID:18760349]

19. Monroy CA, Mackie DI, Roman DL. (2013) A high throughput screen for RGS proteins using steady state monitoring of free phosphate formation. PLoS ONE, 8 (4): e62247. [PMID:23626793]

20. Roof RA, Jin Y, Roman DL, Sunahara RK, Ishii M, Mosberg HI, Neubig RR. (2006) Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins. Chem Biol Drug Des, 67 (4): 266-74. [PMID:16629824]

21. Saitoh O, Kubo Y, Miyatani Y, Asano T, Nakata H. (1997) RGS8 accelerates G-protein-mediated modulation of K+ currents. Nature, 390 (6659): 525-9. [PMID:9394004]

22. Saitoh O, Kubo Y, Odagiri M, Ichikawa M, Yamagata K, Sekine T. (1999) RGS7 and RGS8 differentially accelerate G protein-mediated modulation of K+ currents. J. Biol. Chem., 274 (14): 9899-904. [PMID:10092682]

23. Saitoh O, Masuho I, Itoh M, Abe H, Komori K, Odagiri M. (2003) Distribution of regulator of G protein signaling 8 (RGS8) protein in the cerebellum. Cerebellum, 2 (2): 154-60. [PMID:12880183]

24. Saitoh O, Masuho I, Terakawa I, Nomoto S, Asano T, Kubo Y. (2001) Regulator of G protein signaling 8 (RGS8) requires its NH2 terminus for subcellular localization and acute desensitization of G protein-gated K+ channels. J. Biol. Chem., 276 (7): 5052-8. [PMID:11087736]

25. Saitoh O, Murata Y, Odagiri M, Itoh M, Itoh H, Misaka T, Kubo Y. (2002) Alternative splicing of RGS8 gene determines inhibitory function of receptor type-specific Gq signaling. Proc. Natl. Acad. Sci. U.S.A., 99 (15): 10138-43. [PMID:12110731]

26. Saitoh O, Odagiri M. (2003) RGS8 expression in developing cerebellar Purkinje cells. Biochem. Biophys. Res. Commun., 309 (4): 836-42. [PMID:13679049]

27. Saitoh O, Yoshihiro K. (2004) Biochemical and electrophysiological analyses of RGS8 function. Meth. Enzymol., 390: 129-48. [PMID:15488175]

28. Sood R, Bonner TI, Makalowska I, Stephan DA, Robbins CM, Connors TD, Morgenbesser SD, Su K, Faruque MU, Pinkett H et al.. (2001) Cloning and characterization of 13 novel transcripts and the human RGS8 gene from the 1q25 region encompassing the hereditary prostate cancer (HPC1) locus. Genomics, 73 (2): 211-22. [PMID:11318611]

29. Sun H, Calipari ES, Beveridge TJ, Jones SR, Chen R. (2015) The brain gene expression profile of dopamine D2/D3 receptors and associated signaling proteins following amphetamine self-administration. Neuroscience, 307: 253-61. [PMID:26321241]

30. Taylor VG, Bommarito PA, Tesmer JJ. (2016) Structure of the Regulator of G Protein Signaling 8 (RGS8)-Gαq Complex: MOLECULAR BASIS FOR Gα SELECTIVITY. J. Biol. Chem., 291 (10): 5138-45. [PMID:26755720]

31. Tuggle K, Ali MW, Salazar H, Hooks SB. (2014) Regulator of G protein signaling transcript expression in human neural progenitor differentiation: R7 subfamily regulation by DNA methylation. Neurosignals, 22 (1): 43-51. [PMID:24903911]

32. Turner EM, Blazer LL, Neubig RR, Husbands SM. (2012) Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med Chem Lett, 3 (2): 146-150. [PMID:22368763]

33. Villasenor A, Wang ZV, Rivera LB, Ocal O, Asterholm IW, Scherer PE, Brekken RA, Cleaver O, Wilkie TM. (2010) Rgs16 and Rgs8 in embryonic endocrine pancreas and mouse models of diabetes. Dis Model Mech, 3 (9-10): 567-80. [PMID:20616094]


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