RGS2 is thought to have protective effects against myocardial hypertrophy as well as atrial arrhythmias.[3][4] Increased stimulation of Gs coupled β1-adrenergic receptors and Gq coupled α1-adrenergic receptors in the heart can result in cardiac hypertrophy.[3] In the case of Gq protein coupled receptor (GqPCR) mediated hypertrophy, Gαq will activate the intracellular affectors phospholipase Cβ and rho guanine nucleotide exchange factor to stimulate cell processes which lead to cardiomyocyte hypertrophy.[3][5] RGS2 functions as a GTPase Activating Protein (GAP) which acts to increase the natural GTPase activity of the Gα subunit.[3][5] By increasing the GTPase activity of the Gα subunit, RGS2 promotes GTP hydrolysis back to GDP, thus converting the Gα subunit back to its inactive state and reducing its signalling ability.[5] Both GsPCR and GqPCR activation can contribute to cardiac hypertrophy via activation of MAP Kinases as well. RGS2 has been shown to decrease phosphorylation of those MAP kinases and therefore decrease their activation in response to Gαs signalling.[3]
In the case of GsPCR mediated hypertrophy, the main mechanism by which signalling contributes to hypertrophy is through the Gβγ subunit; Gαs signalling by itself is not sufficient.[6] Nevertheless, RGS2 has been shown to inhibit Gs mediated hypertrophy. The mechanism of how RGS2 regulates increased Gβγ signalling is not well understood, apart from the fact that it is unrelated to RGS2’s GAP function.[6] A deficiency in RGS2 has been linked with increased cardiac hypertrophy in mice.[3] RGS2 deficient hearts appear normal until confronted with an increased workload, to which they respond readily with increased Gαq signalling and hypertrophy.[3][6]
Gαs subunits increase adenyl cyclase activity, which in turn leads to cAMP accumulation in the myocyte nucleus to trigger hypertrophy. RGS2 regulates the effects of increased Gαs signalling through its GAP function.[3] Stimulation of GsPCRs not only leads to hypertrophy but it has also been shown to selectively induce higher expression levels of RGS2 which in turn, protects against hypertrophy, providing a mechanism for maintaining homeostatic conditions.[3]
There has also been some evidence of a role of RGS2 in atrial arrhythmias where RGS2 deficient mice exhibited prolonged and greater susceptibility to electrically induced atrial fibrillation.[4] This was attributed to a decrease in RGS2’s inhibitory effects on Gq coupled M3 muscarinic receptor signalling, resulting in increased Gαq activity.[4] The M3 muscarinic receptor normally activates delayed rectifier potassium channels in the atria, thus increased Gαq activity is thought to result in an altered potassium flux, a decreased refractory period, increased chance of current re-entry and inappropriate contraction.[4]
↑ 4.04.14.24.3Tuomi JM, Chidiac P, Jones DL (February 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. doi:10.1152/ajpheart.00779.2009. PMID19966055.
↑ 6.06.16.2Vidal M, Wieland T, Lohse MJ, Lorenz K (November 2012). "β-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gβγ/Erk-dependent pathway". Cardiovasc. Res. 96 (2): 255–64. doi:10.1093/cvr/cvs249. PMID22843704.
↑Wieland T, Lutz S, Chidiac P (April 2007). "Regulators of G protein signalling: a spotlight on emerging functions in the cardiovascular system". Curr Opin Pharmacol. 7 (2): 201–7. doi:10.1016/j.coph.2006.11.007. PMID17276730.
↑Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME, Tang M, Wang G (December 2003). "Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure". Nat. Med. 9 (12): 1506–12. doi:10.1038/nm958. PMID14608379.
↑Salim S, Sinnarajah S, Kehrl JH, Dessauer CW (May 2003). "Identification of RGS2 and type V adenylyl cyclase interaction sites". J. Biol. Chem. 278 (18): 15842–9. doi:10.1074/jbc.M210663200. PMID12604604.
Further reading
Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (1991). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA Cell Biol. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID1702972.
Wu HK, Heng HH, Shi XM, et al. (1995). "Differential expression of a basic helix-loop-helix phosphoprotein gene, G0S8, in acute leukemia and localization to human chromosome 1q31". Leukemia. 9 (8): 1291–8. PMID7643615.
Druey KM, Blumer KJ, Kang VH, Kehrl JH (1996). "Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family". Nature. 379 (6567): 742–6. doi:10.1038/379742a0. PMID8602223.
Siderovski DP, Hessel A, Chung S, et al. (1996). "A new family of regulators of G-protein-coupled receptors?". Curr. Biol. 6 (2): 211–2. doi:10.1016/S0960-9822(02)00454-2. PMID8673468.
Heximer SP, Cristillo AD, Forsdyke DR (1997). "Comparison of mRNA expression of two regulators of G-protein signaling, RGS1/BL34/1R20 and RGS2/G0S8, in cultured human blood mononuclear cells". DNA Cell Biol. 16 (5): 589–98. doi:10.1089/dna.1997.16.589. PMID9174164.
Tseng CC, Zhang XY (1998). "Role of regulator of G protein signaling in desensitization of the glucose-dependent insulinotropic peptide receptor". Endocrinology. 139 (11): 4470–5. doi:10.1210/en.139.11.4470. PMID9794454.
Beadling C, Druey KM, Richter G, et al. (1999). "Regulators of G protein signaling exhibit distinct patterns of gene expression and target G protein specificity in human lymphocytes". J. Immunol. 162 (5): 2677–82. PMID10072511.
Popov SG, Krishna UM, Falck JR, Wilkie TM (2000). "Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trisphosphate-dependent inhibition of regulators of G protein-signaling GTPase-activating protein activity". J. Biol. Chem. 275 (25): 18962–8. doi:10.1074/jbc.M001128200. PMID10747990.
Chatterjee TK, Fisher RA (2000). "Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs". J. Biol. Chem. 275 (31): 24013–21. doi:10.1074/jbc.M002082200. PMID10791963.
Cunningham ML, Waldo GL, Hollinger S, et al. (2001). "Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling". J. Biol. Chem. 276 (8): 5438–44. doi:10.1074/jbc.M007699200. PMID11063746.
Heximer SP, Lim H, Bernard JL, Blumer KJ (2001). "Mechanisms governing subcellular localization and function of human RGS2". J. Biol. Chem. 276 (17): 14195–203. doi:10.1074/jbc.M009942200. PMID11278586.
Mittmann C, Schüler C, Chung CH, et al. (2001). "Evidence for a short form of RGS3 preferentially expressed in the human heart". Naunyn Schmiedebergs Arch. Pharmacol. 363 (4): 456–63. doi:10.1007/s002100000376. PMID11330340.
Mittmann C, Chung CH, Höppner G, et al. (2002). "Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure". Cardiovasc. Res. 55 (4): 778–86. doi:10.1016/S0008-6363(02)00459-5. PMID12176127.
Nlend MC, Bookman RJ, Conner GE, Salathe M (2002). "Regulator of G-protein signaling protein 2 modulates purinergic calcium and ciliary beat frequency responses in airway epithelia". Am. J. Respir. Cell Mol. Biol. 27 (4): 436–45. doi:10.1165/rcmb.2002-0012oc. PMID12356577.
