regulator of G-protein signaling 6 | R7 family | IUPHAR/BPS Guide to PHARMACOLOGY

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regulator of G-protein signaling 6

Target not currently curated in GtoImmuPdb

Target id: 2815

Nomenclature: regulator of G-protein signaling 6

Abbreviated Name: RGS6

Family: R7 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 - 490 14q24.3 RGS6 regulator of G protein signaling 6 19
Mouse - 472 12 D1 Rgs6 regulator of G-protein signaling 6
Rat - 472 6q24 Rgs6 regulator of G-protein signaling 6
Previous and Unofficial Names
RGS6Lalpha1
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the regulator of G-protein signaling domain of RGS6.
PDB Id:  2ES0
Resolution:  2.1Å
Species:  Human
References:  22
Associated Proteins
G Proteins
Name References
Gαi/0 23
Interacting Proteins
Name Effect References
Regulator of microtubule stability stathmin-2 (SCG10) Neuronal differentiation. 12
DNA methyltransferase 1 Interaction with DNMT1 inhibits DNA methyltransferase 1-associated protein 1 (DMAP1). 13
lysine acetyltransferase 5 Degradation of DNMT1 and promotes apoptosis. 10
Tissue Distribution
Brain, heart, liver, colon, kidney, testis, skin and lung.
Species:  Human
Technique:  Immunohistochemistry and RT-PCR.
References:  15,19
Brain, heart, liver and gastrointestinal tract.
Species:  Mouse
Technique:  Immunohistochemistry and Western blot.
References:  23-25
Brain, heart.
Species:  Rat
Technique:  Immunohistochemistry and RT-PCR.
References:  9,12
Functional Assays
Apoptosis assay (Caspase assay, Annexin V assay, and ROS generation etc.).
Species:  Human
Tissue:  Breast cancer.
Response measured:  Apoptosis.
References:  16
Reactive oxygen species (ROS) generation.
Species:  Mouse
Tissue:  Heart.
Response measured:  Apoptosis.
References:  23
Cyclic AMP assay.
Species:  Mouse
Tissue:  Neuron.
Response measured:  Increase in cAMP.
References:  24
Functional Assay Comments
The RGScreenTM Service is a cell-free, high-throughput assay platform for interrogating RGS protein activity/function and which can facilitate screening for modulatory molecules [2,5].
Physiological Functions
Parasympathetic regulation of heart rate, doxorubicin mediated myocardial cell apoptosis and cardiomyopathy, promotes alcohol seeking behaviour.
Species:  Human
Tissue:  Heart.
References:  11,23,25-26
Promotes anxiety and depression, ensures co-ordination of motor movement, adult maintainance of dopaminergic neuron in the ventral substantia nigra.
Species:  Mouse
Tissue:  Brain.
References:  4,15,24
RGS6 variants are associated with dietary fat intake.
Species:  Human
Tissue:  Adipose tissue.
References:  21
Regulates vision.
Species:  Mouse
Tissue:  Retinal depolarizing bipolar cells.
References:  1,20
Inhibition of cancer cell growth, colony formation and stimulation of apoptosis, ATM and p53 activation by a ROS dependent mechanism.
Species:  Human
Tissue:  Breast cancer.
References:  11,16
RGS6 variants are associated with a reduced risk of bladder cancer.
Species:  Human
Tissue:  Bladder cancer.
References:  3
Physiological Consequences of Altering Gene Expression
Mice with RGS6 knockout display enhanced carbachol-induced bradycardia and muscarinic inhibition of spontaneous action potential firing rate of SA nodal cells, reduction in time course of IKAch activation and deactivation and extent of desensitization in atrial myocytes. RGS6 knockout ameliorates alcohol seeking and protects against alcohol induced cardiomyopathy and cell death in heart. RGS6-null mice have no gross abnormalities. They do however, have low blood pressure without change in heart rate, and decreased body weight compared to wild-type animals.
Species:  Mouse
Tissue:  Haert.
Technique:  Gene knockout.
References:  17,23,25
RGS6 knockout (RGS-/-) mice exhibit altered gait and ataxia.
Species:  Mouse
Tissue:  Brain (cerebellum).
Technique:  Gene knockout.
References:  15,20,23
RGS knockout (RGS-/-) mice exhibit neuronal loss and molecular features of degenerating ventral substantia nigra compacta (vSNc) neurons. These mice show selective unilateral degeneration of SNc and progressive degeneration and loss of midbrain dopaminergic (mDA) neurons.
Species:  Mouse
Tissue:  Midbrain.
Technique:  Gene knockout.
References:  4
RGS6 knockout ameliorates alcoholic hepatic steatosis and apoptosis.
Species:  Mouse
Tissue:  Liver.
Technique:  Gene knockout.
References:  23
RGS6 null mice exhibit a reduction in alcohol induced gastrointestinal apoptosis and endotoxemia.
Species:  Mouse
Tissue:  Gastrointestinal mucosa.
Technique:  Gene knockout.
References:  23
RGS6 knockout regulates dopamine bioavailibility which contributes to alcohol seeking behaviour.
Species:  Mouse
Tissue:  VTA neurons.
Technique:  Gene knockout.
References:  23
RGS6 null mice exhibit resistance to doxorubicin induced growth and apoptosis in MEFs.
Species:  Mouse
Tissue:  Mouse embryonic fibroblasts (MEFs).
Technique:  Gene knockout.
References:  16
RGS6 null mice exhibit defective retinal depolarizing bipolar cells.
Species:  Mouse
Tissue:  Retinal bipolar cells.
Technique:  Gene knockout.
References:  20
RGS6 null mice develop spontaneous tumor upon 7,12-dimethylbenza[αα]anthracene (DMBA) treatment.
Species:  Mouse
Tissue:  Mammary glands and cancerous cells developed therein.
Technique:  Gene knockout.
References:  14
Xenobiotics Influencing Gene Expression
Doxorubicin treatment upregulates RGS6 expression.
Species:  Mouse
Tissue:  MCF-7 (breast cancer cell line) xenograft.
Technique:  Western blot and immunohistochemistry.
References:  11
Xenobiotics Influencing Gene Expression
RGS6 expression is downregulated in gemcitabine-resistant human cholangiocarcinoma cell lines, as determined by micoarray analysis [18].
Clinically-Relevant Mutations and Pathophysiology
Disease:  Alcoholic liver disease
Description: Alcoholic liver disease encompasses the hepatic pathologies attributable to alcohol overconsumption. Such manifestations include fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis.
Synonyms: alcoholic hepatosteatosis
Role: 
References:  23
Disease:  Anxiety
OMIM: 607834
Role: 
References:  24
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
Role: 
References:  14,16
Disease:  Cardiovascular disease
Comments: 
References:  23,26
Disease:  Parkinson Disease
Synonyms: Parkinson's disease [Disease Ontology: DOID:14330]
Disease Ontology: DOID:14330
OMIM: 168600
Role: 
References:  4
Biologically Significant Variants
Type:  Naturally occurring SNP
Species:  Human
Description:  The c.1369-1G>C variant identified in the acceptor splice site within intron 16 of RGS6 is associated with congenital cataract development.
References:  8
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant (isoform 3, also known as RGS6Lbeta1) results in a frame-shift creating a a distinct C-terminus compared to isoform 1.
Amino acids:  485
Nucleotide accession: 
Protein accession: 
References:  7
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant (isoform 2, also known as RGS6Lalpha2) is missing an 18 amino acid segment compared to isoform 1.
Amino acids:  472
Nucleotide accession: 
Protein accession: 
References:  7
Type:  Splice variant
Species:  Human
Description:  Affects subcelllular localization. This splice variant (isoform 4, also known as RGS6Lbeta2) is shorter than isoform 1 and has a distinct C-terminus
Amino acids:  467
Nucleotide accession: 
Protein accession: 
References:  7
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant (isoform 5, also known as RGS6Lalpha1(-GGL)) is missing a missing a segment of the GGL domain, making it shorter than isoform 1.
Amino acids:  453
Nucleotide accession: 
Protein accession: 
References:  6
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant (isoform 6, also known as RGS6Lalpha2(-GGL)) is missing 2 internal protein segments, compared to isoform 1.
Amino acids:  435
Nucleotide accession: 
Protein accession: 
References:  6
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant (isoform 7, also known as RGS6Lbeta1(-GGL)) is shorter than isoform 1. and has a distinct C-terminus.
Amino acids:  448
Nucleotide accession: 
Protein accession: 
References:  6
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant represents isoform 8, also known as RGS6Lbeta2(-GGL).
Amino acids:  430
Nucleotide accession: 
Protein accession: 
References:  6
Type:  Splice variant
Species:  Human
Description:  Affects subcellular localization. This splice variant represents isoform 9 which has a shorter N-terminus compared to isoform 1.
Amino acids:  437
Nucleotide accession: 
Protein accession: 
References:  6
Type:  Splice variant
Species:  Human
Description:  Subcellular distribution patterns ranging from an exclusive cytoplasmic to exclusive nuclear/nucleolar localization. The protein generated from these transcripts (isoform 1) is the longest isoform at 490 amino acids.
Amino acids:  490
Nucleotide accession: 
Protein accession: 
References:  7
Type:  Naturally occurring SNP
Species:  Human
Description:  A SNP in the 3' UTR of RGS6 modulates the risk of bladder cancer.
Nucleotide change:  C>T
SNP accession: 
References:  3
Type:  Naturally occurring SNPs
Species:  Human
Description:  It is reported that certain RGS6 SNPs may underlie a behavioural tendency toward fat-laden food intake.
SNP accession: 
References:  21

References

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1. Anderson GR, Posokhova E, Martemyanov KA. (2009) The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling. Cell Biochem. Biophys., 54 (1-3): 33-46. [PMID:19521673]

2. BellBrook Labs. RGScreenTMService. Accessed on 25/08/2015. Modified on 25/08/2015. BellBrook Labs, http://www.bellbrooklabs.com/partnering-sidemenu-bio/partnering-sidemenu-bio-rgscreen

3. Berman DM, Wang Y, Liu Z, Dong Q, Burke LA, Liotta LA, Fisher R, Wu X. (2004) A functional polymorphism in RGS6 modulates the risk of bladder cancer. Cancer Res., 64 (18): 6820-6. [PMID:15375002]

4. Bifsha P, Yang J, Fisher RA, Drouin J. (2014) Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra. PLoS Genet., 10 (12): e1004863. [PMID:25501001]

5. Bosch DE, Zielinski T, Lowery RG, Siderovski DP. (2012) Evaluating modulators of "Regulator of G-protein Signaling" (RGS) proteins. Curr Protoc Pharmacol, Chapter 2: Unit2.8. [PMID:22382998]

6. Chatterjee TK, Eapen A, Kanis AB, Fisher RA. (1997) Genomic organization, 5'-flanking region, and chromosomal localization of the human RGS3 gene. Genomics, 45 (2): 429-33. [PMID:9344672]

7. Chatterjee TK, Liu Z, Fisher RA. (2003) Human RGS6 gene structure, complex alternative splicing, and role of N terminus and G protein gamma-subunit-like (GGL) domain in subcellular localization of RGS6 splice variants. J. Biol. Chem., 278 (32): 30261-71. [PMID:12761221]

8. Chograni M, Alkuraya FS, Maazoul F, Lariani I, Chaabouni-Bouhamed H. (2015) RGS6: a novel gene associated with congenital cataract, mental retardation, and microcephaly in a Tunisian family. Invest. Ophthalmol. Vis. Sci., 56 (2): 1261-6. [PMID:25525169]

9. Doupnik CA, Xu T, Shinaman JM. (2001) Profile of RGS expression in single rat atrial myocytes. Biochim. Biophys. Acta, 1522 (2): 97-107. [PMID:11750060]

10. Huang J, Stewart A, Maity B, Hagen J, Fagan RL, Yang J, Quelle DE, Brenner C, Fisher RA. (2014) RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis. Oncogene, 33 (27): 3604-11. [PMID:23995786]

11. Huang J, Yang J, Maity B, Mayuzumi D, Fisher RA. (2011) Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism. Cancer Res., 71 (20): 6310-9. [PMID:21859827]

12. Liu Z, Chatterjee TK, Fisher RA. (2002) RGS6 interacts with SCG10 and promotes neuronal differentiation. Role of the G gamma subunit-like (GGL) domain of RGS6. J. Biol. Chem., 277 (40): 37832-9. [PMID:12140291]

13. Liu Z, Fisher RA. (2004) RGS6 interacts with DMAP1 and DNMT1 and inhibits DMAP1 transcriptional repressor activity. J. Biol. Chem., 279 (14): 14120-8. [PMID:14734556]

14. Maity B, Stewart A, O'Malley Y, Askeland RW, Sugg SL, Fisher RA. (2013) Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression. Carcinogenesis, 34 (8): 1747-55. [PMID:23598467]

15. Maity B, Stewart A, Yang J, Loo L, Sheff D, Shepherd AJ, Mohapatra DP, Fisher RA. (2012) Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling. J. Biol. Chem., 287 (7): 4972-81. [PMID:22179605]

16. Maity B, Yang J, Huang J, Askeland RW, Bera S, Fisher RA. (2011) Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity. J. Biol. Chem., 286 (2): 1409-19. [PMID:21041304]

17. Posokhova E, Wydeven N, Allen KL, Wickman K, Martemyanov KA. (2010) RGS6/Gβ5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate. Circ. Res., 107 (11): 1350-4. [PMID:20884879]

18. Sato J, Kimura T, Saito T, Anazawa T, Kenjo A, Sato Y, Tsuchiya T, Gotoh M. (2011) Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma. J Hepatobiliary Pancreat Sci, 18 (5): 700-11. [PMID:21451941]

19. Seki N, Hattori A, Hayashi A, Kozuma S, Hori T, Saito T. (1999) The human regulator of G-protein signaling protein 6 gene (RGS6) maps between markers WI-5202 and D14S277 on chromosome 14q24.3. J. Hum. Genet., 44 (2): 138-40. [PMID:10083744]

20. Shim H, Wang CT, Chen YL, Chau VQ, Fu KG, Yang J, McQuiston AR, Fisher RA, Chen CK. (2012) Defective retinal depolarizing bipolar cells in regulators of G protein signaling (RGS) 7 and 11 double null mice. J. Biol. Chem., 287 (18): 14873-9. [PMID:22371490]

21. Sibbel SP, Talbert ME, Bowden DW, Haffner SM, Taylor KD, Chen YD, Wagenknecht LE, Langefeld CD, Norris JM. (2011) RGS6 variants are associated with dietary fat intake in Hispanics: the IRAS Family Study. Obesity (Silver Spring), 19 (7): 1433-8. [PMID:21233807]

22. Soundararajan M, Willard FS, Kimple AJ, Turnbull AP, Ball LJ, Schoch GA, Gileadi C, Fedorov OY, Dowler EF, Higman VA et al.. (2008) Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits. Proc. Natl. Acad. Sci. U.S.A., 105 (17): 6457-62. [PMID:18434541]

23. Stewart A, Maity B, Anderegg SP, Allamargot C, Yang J, Fisher RA. (2015) Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol. Proc. Natl. Acad. Sci. U.S.A., 112 (7): E786-95. [PMID:25646431]

24. Stewart A, Maity B, Wunsch AM, Meng F, Wu Q, Wemmie JA, Fisher RA. (2014) Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis. FASEB J., 28 (4): 1735-44. [PMID:24421401]

25. Yang J, Huang J, Maity B, Gao Z, Lorca RA, Gudmundsson H, Li J, Stewart A, Swaminathan PD, Ibeawuchi SR et al.. (2010) RGS6, a modulator of parasympathetic activation in heart. Circ. Res., 107 (11): 1345-9. [PMID:20864673]

26. Yang J, Maity B, Huang J, Gao Z, Stewart A, Weiss RM, Anderson ME, Fisher RA. (2013) G-protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin. Cancer Res., 73 (6): 1662-7. [PMID:23338613]

Contributors

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How to cite this page

Bandana Chakravarti, Rory A. Fisher.
R7 family: regulator of G-protein signaling 6. Last modified on 08/05/2017. Accessed on 26/03/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2815.