regulator of G-protein signaling 2

Target id: 2808

Nomenclature: regulator of G-protein signaling 2

Abbreviated Name: RGS2

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

   GtoImmuPdb view: OFF :     Currently no data for regulator of G-protein signaling 2 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 211 1q31 RGS2 regulator of G protein signaling 2
Mouse - 211 1 F Rgs2 regulator of G-protein signaling 2
Rat - 211 13q21 Rgs2 regulator of G-protein signaling 2
Previous and Unofficial Names
G0S8 (human) | G0/G1 switch regulatory protein 8 | cell growth-inhibiting gene 31 protein
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
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 RGS2.
PDB Id:  2AF0
Resolution:  2.3Å
Species:  Human
References:  38
Associated Proteins
G Proteins
Name References
Gαi/0
Gαq/11
Interacting Proteins
Name Effect References
Protein kinase G (PKG) 1 RGS2 phosphorylation, blunting RGS2 degradation, promotes RGS2 membrane localization. 27
adenylyl cyclase Inhibits cAMP production. 31,33
α1A-adrenoceptor Inhibition of α1A-adrenoceptor signaling. 9
M1 receptor Inhibits M1 mAChR-mediated signalling (carbachol-stimulated PIP2 hydrolysis and inositol 1,4,5-trisphosphate accumulation). 1
Nek7 Mitotic spindle organization. 5
leucine rich repeat kinase 2 Control of neuronal process length, protective against neuronal toxicity. 6
TRPV6 Modulates channel activity. 34
eIF2Bε Controls protein synthesis. 24
Tissue Distribution
Brain, heart, lung, kidney, intestine, lymphocyte, placenta, testis.
Species:  Human
Technique:  SybrGreen PCR.
References:  18
Heart.
Species:  Human
Technique:  Western blot.
References:  39
Heart, brain, spleen, lung, skeletal muscle, kidney, testis, adrenal gland, ovary, intestine.
Species:  Mouse
Technique:  Northern blot, RT-PCR.
References:  4,17,34
Brain, heart, lung.
Species:  Mouse
Technique:  Western blot.
References:  16,44
Osteoblast.
Species:  Mouse
Technique:  Immunofluorescence.
References:  32
Brain, heart, spleen, liver, skeletal muscle, kidney, and testis.
Species:  Rat
Technique:  Northern blot.
References:  22
Heart.
Species:  Rat
Technique:  Western blot.
References:  36
Functional Assays
G protein binding, accelerates GTP hydrolysis by Gqα and inhibition of Gqα-mediated activation of PLCβ
Species:  None
Tissue:  Biochemical assay with purified protein.
Response measured:  Rgs2 binds to Gq and inhibits accumulation of [3H]phosphatidyl inositol 1,4,5-trisphosphate (IP3) produced by phospholipase C-β1.
References:  12-13,15
Inhibition of carbachol-induced IP3 production.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  Reduced IP3 production.
References:  12
Gq-mediated intracellular calcium mobilization.
Species:  Human
Tissue:  HEK293T cells.
Response measured:  Inhibit Ca2+ signaling by Gαq/11-coupled M3 mAChRs.
References:  2
ERK1/2 activation attenuation in response to both endothelin-1 and isoproterenol.
Species:  Rat
Tissue:  Neonatal ventricular cardiomyocytes.
Response measured:  Reduced ERK1/2 phosphorylation.
References:  25
Reduced cAMP stimulation in response to β adrenergic receptor activation by isoproterenol (NB human and rat studied).
Species:  Human
Tissue:  Neonatal ventricular cardiomyocytes or HEK293T cells.
Response measured:  Reduction of cAMP response.
References:  25,29
Physiological Functions
Inhibit cell growth in vitro.
Species:  Human
Tissue:  MCF7 and HEK293T cells.
References:  21
Modulation of vasoconstrictor responses and blood pressure in vivo. (NB human and mouse studied).
Species:  Human
Tissue:  Cardiovascular system, kidney, peripheral blood mononuclear cells, fibroblasts.
References:  8,10,35,40
Regulation of bone formation by osteoblasts.
Species:  Mouse
Tissue:  Osteoblasts.
References:  32
Physiological Consequences of Altering Gene Expression
RGS2 knock-out mice develop hypertension phenotype.
Species:  Mouse
Tissue: 
Technique:  Gene knock-out.
References:  7,11,40
RGS2 knock-out caused spontaneous airway hyper responsiveness in mice,
Species:  Mouse
Tissue:  Lung.
Technique:  Gene knock-out.
References:  42
RGS2 deficient mice display increased anxiety responses, depression-like behaviour, reduced T cell proliferation and IL-2 production.
Species:  Mouse
Tissue:  Brain, T cells.
Technique:  Gene knock-out.
References:  20,26
RGS2 deficient mice have enhanced susceptibility to atrial tachycardia/fibrillation (AT/F) via enhanced M3 muscarinic receptor activity.
Species:  Mouse
Tissue:  Heart.
Technique:  Gene knock-out.
References:  41
RGS2 mRNA and protein levels are elevated in mononuclear cells from patients with Bartter's/Gitelman's syndrome. These patients show hyporesponsiveness to pressor agonists, are hypo/normotensive, and display altered vascular tone regulation.
Species:  Human
Tissue:  Mononuclear cells.
Technique:  RT-PCR and Western blot.
References:  3
RGS2 deficiency worsens kidney fibrosis and inflammation following unilateral ureteral obstruction (UUO) in mice. RGS2 deletion in bone marrow aggravates UUO-induced kidney fibrosis.
Species:  Mouse
Tissue:  Kidney.
Technique:  Gene knock-out.
References: 
RGS2 suppresses breast cancer cell growth: high RGS2 expression in non-invasive cells, low expression in invasive cells. Invasiveness can be prevented by overexpression of RGS2.
Species:  Mouse
Tissue:  MCF10A and MCF7 cells.
Technique:  Gene over-expression
References:  21
Xenobiotics Influencing Gene Expression
Type 1α protein kinase G inhibitor (Rp-8-pCPT-cGMPS) treatment stabilizes RGS2 protein.
Species:  Mouse
Tissue:  A7r5 vascular smooth muscle cells.
Technique:  Western blot.
References:  27
Proteasome inhibitor (MG-132, lactacystin) or cardiotonic steroids (digoxin, ouabain) treatment increases protein levels.
Species:  Human
Tissue:  HEK293T, HEK293FT and MCF7 cells.
Technique:  Western blot, PathHunter ProLabel β-galactosidase complementation assay.
References:  2,21,36
Proteasome inhibitors (MG-132, lactacystin) or cardiotonic steroids (digoxin, ouabain) treatment increase protein levels.
Species:  Rat
Tissue:  Primary aortic vascular smooth muscle cells.
Technique:  Western blot.
References:  36
Protein kinase C activator (indolactam V, PMA) treatment increases protein levels.
Species:  Human
Tissue:  HEK293T cells.
Technique:  Western blot, PathHunter ProLabel β-galactosidase complementation assay.
References:  29
Protein kinase C activator (Indolactam V, PMA) treatment increases protein levels.
Species:  Rat
Tissue:  Primary aortic vascular smooth muscle cells.
Technique:  Western blot.
References:  29
Clinically-Relevant Mutations and Pathophysiology
Disease:  Anxiety
OMIM: 607834
Comments: 
References:  14,19,23,28,37
Disease:  Hypertension, essential
Disease Ontology: DOID:10825
OMIM: 145500
References:  11,30,40,43

References

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1. Bernstein LS, Ramineni S, Hague C, Cladman W, Chidiac P, Levey AI, Hepler JR. (2004) RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. J. Biol. Chem.279 (20): 21248-56. [PMID:14976183]

2. Bodenstein J, Sunahara RK, Neubig RR. (2007) N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Mol. Pharmacol.71 (4): 1040-50. [PMID:17220356]

3. Calò LA, Pagnin E, Davis PA, Sartori M, Ceolotto G, Pessina AC, Semplicini A. (2004) Increased expression of regulator of G protein signaling-2 (RGS-2) in Bartter's/Gitelman's syndrome. A role in the control of vascular tone and implication for hypertension. J. Clin. Endocrinol. Metab.89 (8): 4153-7. [PMID:15292363]

4. Chen C, Zheng B, Han J, Lin SC. (1997) Characterization of a novel mammalian RGS protein that binds to Galpha proteins and inhibits pheromone signaling in yeast. J. Biol. Chem.272 (13): 8679-85. [PMID:9079700]

5. de Souza EE, Hehnly H, Perez AM, Meirelles GV, Smetana JH, Doxsey S, Kobarg J. (2015) Human Nek7-interactor RGS2 is required for mitotic spindle organization. Cell Cycle14 (4): 656-67. [PMID:25664600]

6. Dusonchet J, Li H, Guillily M, Liu M, Stafa K, Derada Troletti C, Boon JY, Saha S, Glauser L, Mamais A et al.. (2014) A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity. Hum. Mol. Genet.23 (18): 4887-905. [PMID:24794857]

7. Gross V, Tank J, Obst M, Plehm R, Blumer KJ, Diedrich A, Jordan J, Luft FC. (2005) Autonomic nervous system and blood pressure regulation in RGS2-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol.288 (5): R1134-42. [PMID:15661972]

8. Gurley SB, Griffiths RC, Mendelsohn ME, Karas RH, Coffman TM. (2010) Renal actions of RGS2 control blood pressure. J. Am. Soc. Nephrol.21 (11): 1847-51. [PMID:20847141]

9. Hague C, Bernstein LS, Ramineni S, Chen Z, Minneman KP, Hepler JR. (2005) Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop. J. Biol. Chem.280 (29): 27289-95. [PMID:15917235]

10. Hercule HC, Tank J, Plehm R, Wellner M, da Costa Goncalves AC, Gollasch M, Diedrich A, Jordan J, Luft FC, Gross V. (2007) Regulator of G protein signalling 2 ameliorates angiotensin II-induced hypertension in mice. Exp. Physiol.92 (6): 1014-22. [PMID:17644703]

11. Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, Steinberg TH et al.. (2003) Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J. Clin. Invest.111 (4): 445-52. [PMID:12588882]

12. Heximer SP, Srinivasa SP, Bernstein LS, Bernard JL, Linder ME, Hepler JR, Blumer KJ. (1999) G protein selectivity is a determinant of RGS2 function. J. Biol. Chem.274 (48): 34253-9. [PMID:10567399]

13. Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR. (1997) RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc. Natl. Acad. Sci. U.S.A.94 (26): 14389-93. [PMID:9405622]

14. Hohoff C, Weber H, Richter J, Domschke K, Zwanzger PM, Ohrmann P, Bauer J, Suslow T, Kugel H, Baumann C et al.. (2015) RGS2 ggenetic variation: association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety. Am. J. Med. Genet. B Neuropsychiatr. Genet.168B (3): 211-22. [PMID:25740197]

15. Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow BE, Barnes CA, Lanahan AA, Siderovski DP, Ross EM et al.. (1998) Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity. J. Neurosci.18 (18): 7178-88. [PMID:9736641]

16. Jiang H, Xie Y, Abel PW, Wolff DW, Toews ML, Panettieri Jr RA, Casale TB, Tu Y. (2015) Regulator of G-Protein Signaling 2 Repression Exacerbates Airway Hyper-Responsiveness and Remodeling in Asthma. Am. J. Respir. Cell Mol. Biol.53 (1): 42-9. [PMID:25368964]

17. Kurrasch DM, Huang J, Wilkie TM, Repa JJ. (2004) Quantitative real-time polymerase chain reaction measurement of regulators of G-protein signaling mRNA levels in mouse tissues. Meth. Enzymol.389: 3-15. [PMID:15313556]

18. 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]

19. Leygraf A, Hohoff C, Freitag C, Willis-Owen SA, Krakowitzky P, Fritze J, Franke P, Bandelow B, Fimmers R, Flint J et al.. (2006) Rgs 2 gene polymorphisms as modulators of anxiety in humans?. J Neural Transm113 (12): 1921-5. [PMID:16736243]

20. Lifschytz T, Broner EC, Zozulinsky P, Slonimsky A, Eitan R, Greenbaum L, Lerer B. (2012) Relationship between Rgs2 gene expression level and anxiety and depression-like behaviour in a mutant mouse model: serotonergic involvement. Int. J. Neuropsychopharmacol.15 (9): 1307-18. [PMID:22040681]

21. Lyu JH, Park DW, Huang B, Kang SH, Lee SJ, Lee C, Bae YS, Lee JG, Baek SH. (2015) RGS2 suppresses breast cancer cell growth via a MCPIP1-dependent pathway. J. Cell. Biochem.116 (2): 260-7. [PMID:25187114]

22. Miles RR, Sluka JP, Santerre RF, Hale LV, Bloem L, Boguslawski G, Thirunavukkarasu K, Hock JM, Onyia JE. (2000) Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms. Endocrinology141 (1): 28-36. [PMID:10614620]

23. Mouri K, Hishimoto A, Fukutake M, Nishiguchi N, Shirakawa O, Maeda K. (2010) Association study of RGS2 gene polymorphisms with panic disorder in Japanese. Kobe J Med Sci55 (5): E116-21. [PMID:20847599]

24. Nguyen CH, Ming H, Zhao P, Hugendubler L, Gros R, Kimball SR, Chidiac P. (2009) Translational control by RGS2. J. Cell Biol.186 (5): 755-65. [PMID:19736320]

25. Nunn C, Zou MX, Sobiesiak AJ, Roy AA, Kirshenbaum LA, Chidiac P. (2010) RGS2 inhibits beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Cell. Signal.22 (8): 1231-9. [PMID:20362664]

26. Oliveira-Dos-Santos AJ, Matsumoto G, Snow BE, Bai D, Houston FP, Whishaw IQ, Mariathasan S, Sasaki T, Wakeham A, Ohashi PS et al.. (2000) Regulation of T cell activation, anxiety, and male aggression by RGS2. Proc. Natl. Acad. Sci. U.S.A.97 (22): 12272-7. [PMID:11027316]

27. Osei-Owusu P, Sun X, Drenan RM, Steinberg TH, Blumer KJ. (2007) Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. J. Biol. Chem.282 (43): 31656-65. [PMID:17681944]

28. Otowa T, Shimada T, Kawamura Y, Sugaya N, Yoshida E, Inoue K, Yasuda S, Liu X, Minato T, Tochigi M et al.. (2011) Association of RGS2 variants with panic disorder in a Japanese population. Am. J. Med. Genet. B Neuropsychiatr. Genet.156B (4): 430-4. [PMID:21438143]

29. Raveh A, Schultz PJ, Aschermann L, Carpenter C, Tamayo-Castillo G, Cao S, Clardy J, Neubig RR, Sherman DH, Sjögren B. (2014) Identification of protein kinase C activation as a novel mechanism for RGS2 protein upregulation through phenotypic screening of natural product extracts. Mol. Pharmacol.86 (4): 406-16. [PMID:25086086]

30. Riddle EL, Rana BK, Murthy KK, Rao F, Eskin E, O'Connor DT, Insel PA. (2006) Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Hypertension47 (3): 415-20. [PMID:16432041]

31. Roy AA, Baragli A, Bernstein LS, Hepler JR, Hébert TE, Chidiac P. (2006) RGS2 interacts with Gs and adenylyl cyclase in living cells. Cell. Signal.18 (3): 336-48. [PMID:16095880]

32. Roy AA, Nunn C, Ming H, Zou MX, Penninger J, Kirshenbaum LA, Dixon SJ, Chidiac P. (2006) Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts. J. Biol. Chem.281 (43): 32684-93. [PMID:16950788]

33. Salim S, Sinnarajah S, Kehrl JH, Dessauer CW. (2003) Identification of RGS2 and type V adenylyl cyclase interaction sites. J. Biol. Chem.278 (18): 15842-9. [PMID:12604604]

34. Schoeber JP, Topala CN, Wang X, Diepens RJ, Lambers TT, Hoenderop JG, Bindels RJ. (2006) RGS2 inhibits the epithelial Ca2+ channel TRPV6. J. Biol. Chem.281 (40): 29669-74. [PMID:16895908]

35. Semplicini A, Lenzini L, Sartori M, Papparella I, Calò LA, Pagnin E, Strapazzon G, Benna C, Costa R, Avogaro A et al.. (2006) Reduced expression of regulator of G-protein signaling 2 (RGS2) in hypertensive patients increases calcium mobilization and ERK1/2 phosphorylation induced by angiotensin II. J. Hypertens.24 (6): 1115-24. [PMID:16685212]

36. Sjögren B, Parra S, Heath LJ, Atkins KB, Xie ZJ, Neubig RR. (2012) Cardiotonic steroids stabilize regulator of G protein signaling 2 protein levels. Mol. Pharmacol.82 (3): 500-9. [PMID:22695717]

37. Smoller JW, Paulus MP, Fagerness JA, Purcell S, Yamaki LH, Hirshfeld-Becker D, Biederman J, Rosenbaum JF, Gelernter J, Stein MB. (2008) Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch. Gen. Psychiatry65 (3): 298-308. [PMID:18316676]

38. 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]

39. Takeishi Y, Jalili T, Hoit BD, Kirkpatrick DL, Wagoner LE, Abraham WT, Walsh RA. (2000) Alterations in Ca2+ cycling proteins and G alpha q signaling after left ventricular assist device support in failing human hearts. Cardiovasc. Res.45 (4): 883-8. [PMID:10728414]

40. Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y et al.. (2003) Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat. Med.9 (12): 1506-12. [PMID:14608379]

41. Tuomi JM, Chidiac P, Jones DL. (2010) Evidence for enhanced M3 muscarinic receptor function and sensitivity to atrial arrhythmia in the RGS2-deficient mouse. Am. J. Physiol. Heart Circ. Physiol.298 (2): H554-61. [PMID:19966055]

42. Xie Y, Jiang H, Nguyen H, Jia S, Berro A, Panettieri Jr RA, Wolff DW, Abel PW, Casale TB, Tu Y. (2012) Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness. J. Allergy Clin. Immunol.130 (4): 968-76.e3. [PMID:22704538]

43. Yang J, Kamide K, Kokubo Y, Takiuchi S, Tanaka C, Banno M, Miwa Y, Yoshii M, Horio T, Okayama A et al.. (2005) Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population. J. Hypertens.23 (8): 1497-505. [PMID:16003176]

44. Zhang W, Anger T, Su J, Hao J, Xu X, Zhu M, Gach A, Cui L, Liao R, Mende U. (2006) Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy. J. Biol. Chem.281 (9): 5811-20. [PMID:16380388]

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How to cite this page

Hoa Phan Thi Nhu, Benita Sjögren.
R4 family: regulator of G-protein signaling 2. Last modified on 08/05/2017. Accessed on 12/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2808.