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regulator of G-protein signaling 8

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Target not currently curated in GtoImmuPdb

Target id: 2813

Nomenclature: regulator of G-protein signaling 8

Abbreviated Name: RGS8

Family: R4 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 180 1q25.3 RGS8 regulator of G protein signaling 8
Mouse - 180 1 65.41 cM Rgs8 regulator of G-protein signaling 8
Rat - 180 13q21 Rgs8 regulator of G-protein signaling 8
Database Links Click here for help
Alphafold P57771 (Hs), Q8BXT1 (Mm), P49804 (Rn)
CATH/Gene3D 1.10.196.10
ChEMBL Target CHEMBL2034803 (Hs)
DrugBank Target CHEMBL2034803 (Hs)
Ensembl Gene ENSG00000135824 (Hs), ENSMUSG00000042671 (Mm), ENSRNOG00000002369 (Rn)
Entrez Gene 85397 (Hs), 67792 (Mm), 54297 (Rn)
Human Protein Atlas ENSG00000135824 (Hs)
KEGG Gene hsa:85397 (Hs), mmu:67792 (Mm), rno:54297 (Rn)
OMIM 607189 (Hs)
Pharos P57771 (Hs)
RefSeq Nucleotide NM_001102450 (Hs), NM_026380 (Mm), NM_019344 (Rn)
RefSeq Protein NP_001095920 (Hs), NP_080656 (Mm), NP_062217 (Rn)
UniProtKB P57771 (Hs), Q8BXT1 (Mm), P49804 (Rn)
Wikipedia RGS8 (Hs)
Associated Proteins Click here for help
G Proteins
Name References
Gαi/0, Gαq/11 3,6,16,20,22,28,34,36
G&alphaq 34
Interacting Proteins
Name Effect References
PAR1 RGS8 binds to PAR1 in the presence of Gαo and inhibits PAR1/Gαi/o-mediated adenylyl cyclase and ERK activation. 15
Ataxin-2 Regulates RGS8 translation in purkinje cells 4
M1 receptor 7
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. 5,10
AT1 receptor 31

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CCG-50014 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.0 pIC50 3,29-30,36
⤷ pIC50 5.0 (IC50 1.1x10-5 M) [3,29-30,36]
Description: Inhibition of Gαo binding
CCG-203920 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 4.4 pIC50 36
⤷ pIC50 4.4 (IC50 3.61x10-5 M) [36]
Description: Inhibition of Gαo binding
RGS4 inhibitor 11b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 4.1 pIC50 36
⤷ pIC50 4.1 (IC50 8.35x10-5 M) [36]
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 [21].
Tissue Distribution Click here for help
Embryonic endocrine pancreas and mouse models of diabetes.
Species:  Mouse
Technique:  Green fluorescent protein (GFP) visualization and Immunofluorescence staining.
References:  37
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:  27
NK cells.
Species:  Rat
Technique:  RT-PCR
References:  12
Nucleus accumbens.
Species:  Rat
Technique:  RT-PCR
References:  13
Cerebellar Purkinje cell layer, several midbrain nuclei.
Species:  Rat
Technique:  Northen blot, in situ hybridisation
References:  6,24,38
Physiological Functions Click here for help
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:  15
RGS8 negatively modulates melanin concentrating hormone receptor 1 (MCH1R)-mediated calcium signaling.
Species:  Human
Tissue:  HEK293T cells.
References:  18-19
RGS8 accelerates the modulation of G-protein-coupled inwardly rectifying K+ channels.
Species:  Rat
Tissue:  Sympathetic neurons, Xenopus oocytes, HEK293 cells.
References:  1-2,8,22-25
RGS8 attenuates the G protein–dependent inhibition of N-type calcium (Ca) channels.
Species:  Human
Tissue:  HEK293 cells.
References:  17
Modulates PAR1 and M3 muscarinic acetylcholine receptor cell surface expression.
Species:  Human
Tissue:  HEK293 cells
References:  14
Expression of RGS8 inhibits the growth arrest response to mating pheromone, slowing G1 arrest and differentiation.
Species:  None
Tissue:  Xenopus oocytes
References:  26
In pancreatic acinar cells, Rgs proteins inhibit secretion of digestive enzymes evoked by G protein-coupled-receptor (GPCR) agonists. In an aggressive model of pancreatitis and pancreatic ductal adenocarcinoma (PDA), KCR8-16 mice (global exon 5 deletion of the Rgs domain in both Rgs8 and Rgs16 genes, oncogenic KrasG12D expressed in all pancreatic cells) rapidly progressed to starvation after mild metabolic challenges. The starvation phenotype is caused by a combination of pancreatic insufficiency and hyperactive utilization of fats in liver of malnourished KCR8-16 mice. Dietary pancreatic enzyme supplements reversed malnutrition in KC and KCR8-16 animals, and extended survival slightly, but also increased PDA tumor burden.
Species:  Mouse
Tissue:  Pancreas
References:  39
Physiological Consequences of Altering Gene Expression Click here for help
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:  11
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:  14
Increased expression of RGS8 contributes to dysregulated mGluR1 signaling in spinocerebellar ataxias (SCAs)
Species:  Mouse
Tissue:  Cerebellum
Technique:  Measuring Purkinje cell dendrite growth
References:  38
RGS8 overexpression is associated with decreased depressive-like behavior
Species:  Mouse
Tissue:  Hippocampus
Technique:  Assesed in the forced swim test
References:  9
Xenobiotics Influencing Gene Expression Click here for help
Amphetamine (AMPH) administration significantly downregulate Rgs8 mRNA expression.
Species:  Rat
Tissue:  Nucleus accumbens
Technique:  qRT-PCR
References:  33
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:  35
Clinically-Relevant Mutations and Pathophysiology Click here for help
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
Role:  Mouse studies suggest that Rgs8 is likely to control aspects of islet progenitor cell activation, differentiation and beta-cell expansion in embryos and metabolically stressed adults.
References:  37
Disease:  Prostate cancer
Disease Ontology: DOID:10283
OMIM: 176807
Role:  RGS8 is one of a number of transcripts identified in the hereditary prostate cancer (HPC1) locus.
References:  32
Gene Expression and Pathophysiology Comments
Cancer mutation overview for RGS8 (summary from the TCGA dataset within cbioportal.org):
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

References

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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. Kobayashi Y, Takemoto R, Yamato S, Okada T, Iijima M, Uematsu Y, Chaki S, Saito Y. (2018) Depression-resistant Phenotype in Mice Overexpressing Regulator of G Protein Signaling 8 (RGS8). Neuroscience, 383: 160-169. [PMID:29758252]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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]

26. 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 USA, 99 (15): 10138-43. [PMID:12110731]

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

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

29. Shaw VS, Mohammadi M, Quinn JA, Vashisth H, Neubig RR. (2019) An Interhelical Salt Bridge Controls Flexibility and Inhibitor Potency for Regulators of G-protein Signaling Proteins 4, 8, and 19. Mol Pharmacol, 96 (6): 683-691. [PMID:31543506]

30. Shaw VS, Mohammadiarani H, Vashisth H, Neubig RR. (2018) Differential Protein Dynamics of Regulators of G-Protein Signaling: Role in Specificity of Small-Molecule Inhibitors. J Am Chem Soc, 140 (9): 3454-3460. [PMID:29460621]

31. Song D, Nishiyama M, Kimura S. (2016) Potent inhibition of angiotensin AT1 receptor signaling by RGS8: importance of the C-terminal third exon part of its RGS domain. J Recept Signal Transduct Res, 36 (5): 478-87. [PMID:26754208]

32. 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]

33. 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]

34. 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]

35. 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]

36. 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]

37. 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]

38. Wu QW, Kapfhammer JP. (2020) Modulation of Increased mGluR1 Signaling by RGS8 Protects Purkinje Cells From Dendritic Reduction and Could Be a Common Mechanism in Diverse Forms of Spinocerebellar Ataxia. Front Cell Dev Biol, 8: 569889. [PMID:33553137]

39. Zolghadri Y, Pal Choudhuri S, Ocal O, Layeghi-Ghalehsoukhteh S, Berhe F, Hale MA, Wilkie TM. (2018) Malnutrition in Pancreatic Ductal Adenocarcinoma (PDA): Dietary Pancreatic Enzymes Improve Short-Term Health but Stimulate Tumor Growth. Am J Pathol, 188 (3): 616-626. [PMID:29248457]

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