Volume 26, Issue 2 (June 2022)                   Physiol Pharmacol 2022, 26(2): 178-187 | Back to browse issues page

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Goharinia M, Mirkhani H. RGS4 inhibition and the effects of adrenoceptor and cholinoceptor agonists on isolated left atrium and aorta of normal and diabetic rats. Physiol Pharmacol. 2022; 26 (2) :178-187
URL: http://ppj.phypha.ir/article-1-1696-en.html
Abstract:   (834 Views)
Introduction: “Regulator of G protein signaling” (RGS) proteins are a family of various proteins that are expressed in different tissues and accelerate hydrolysis rate of GTP to GDP by several thousand-fold increase in GTPase activity of Gα subunit. Thus, they act as negative regulators of G protein-coupled receptors (GPCRs) signaling. In this study, the effect of CCG-50014, a RGS4 inhibitor, on isolated aorta and left atrium of normal and diabetic rats has been investigated. Methods: Isolated aorta was treated with increasing concentrations of phenylephrine and acetylcholine. Isolated left atrium was treated with increasing concentrations of acetylcholine and isoprenaline; both in the absence and presence of CCG-50014. The pEC50 (negative logarithm of the concentration which produces half maximal response) and maximum response of each compound were extracted from concentration-response curves. Results: Pre-treatment of aorta with CCG-50014 had no important effect on the response to phenylephrine and acetylcholine. CCG-50014 decreased isoprenaline inotropic potency on normal atrium but had no effect on its maximum response. In diabetic atrium, CCG-50014 dramatically reduced both the pEC50 and maximum response of isoprenaline. CCG-50014 did not affect normal atrium response to acetylcholine but in diabetic atrium, it caused a small yet significant decrease in the pEC50 of acetylcholine while increased its maximum relaxing effect. Conclusion: It seems that RGS4 is not involved in the termination of GPCRs signaling in rat aorta. In atrium, RGS4 inhibition unexpectedly results in attenuation of β-adrenoceptormediated atrial contractility, which is much more prominent in diabetes.
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1. Ajay M, Achike FI, Mustafa AM, Mustafa MR. Effect of quercetin on altered vascular reactivity in aortas isolated from streptozotocin-induced diabetic rats. Diabetes Res Clin Pract 2006; 73: 1-7. [DOI:10.1016/j.diabres.2005.11.004]
2. Altan VM, Arioglu E, Guner S, Ozcelikay AT. The influence of diabetes on cardiac betaadrenoceptor subtypes. Heart Fail Rev 2007; 12: 58-65. [DOI:10.1007/s10741-007-9005-6]
3. Blazer LL, Zhang H, Casey EM, Husbands SM, Neubig RR. A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. Biochem 2011; 50: 3181-92. [DOI:10.1021/bi1019622]
4. Carrier GO, Edwards AD, Aronstam RS. Cholinergic supersensitivity and decreased number of muscarinic receptors in atria from short-term diabetic rats. J Mol Cell Cardiol 1984; 16: 963-5. [DOI:10.1016/S0022-2828(84)80032-2]
5. Chen IS, Furutani K, Inanobe A, Kurachi Y. RGS4 regulates partial agonism of the M2 muscarinic receptor-activated K+ currents. J Physiol 2014; 592: 1237-48. [DOI:10.1113/jphysiol.2013.269803]
6. Cho H, Harrison K, Schwartz O, Kehrl JH. The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1- phosphate, angiotensin II and endothelin-1 signalling. Biochem J 2003; 371: 973-80. [DOI:10.1042/bj20021769]
7. Dall'ago P, Schaan BD, da Silva VO, Werner J, da Silva Soares PP, de Angelis K, et al. Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats. Auton Neurosci 2007; 131: 28-35. [DOI:10.1016/j.autneu.2006.06.005]
8. Gu S, Cifelli C, Wang S, Heximer SP. RGS proteins: identifying new GAPs in the understanding of blood pressure regulation and cardiovascular function. Clin Sci 2009; 116: 391-9. [DOI:10.1042/CS20080272]
9. Hao J, Michalek C, Zhang W, Zhu M, Xu X, Mende U. Regulation of cardiomyocyte signaling by RGS proteins: differential selectivity towards G proteins and susceptibility to regulation. J Mol Cell Cardiol 2006; 41: 51-61. [DOI:10.1016/j.yjmcc.2006.04.003]
10. Hendriks-Balk MC, Peters SL, Michel MC, Alewijnse AE. Regulation of G protein-coupled receptor signalling: focus on the cardiovascular system and regulator of G protein signalling proteins. Eur J Pharmacol 2008; 585: 278-91. [DOI:10.1016/j.ejphar.2008.02.088]
11. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001; 88: 14-22. [DOI:10.1161/01.RES.88.2.e14]
12. Kazuyama E, Saito M, Kinoshita Y, Satoh I, Dimitriadis F, Satoh K. Endothelial dysfunction in the early- and late-stage type-2 diabetic Goto-Kakizaki rat aorta. Mol Cell Biochem 2009; 332: 95-102. [DOI:10.1007/s11010-009-0178-2]
13. Kimple AJ, Bosch DE, Giguere PM, Siderovski DP. Regulators of G-protein signaling and their Galpha substrates: promises and challenges in their use as drug discovery targets. Pharmacol Rev 2011; 63: 728-49. [DOI:10.1124/pr.110.003038]
14. Kofo-Abayomi A, Lucas PD. Muscarinic receptor density is reduced in diabetic rat atria, an effect prevented by the aldose reductase inhibitor, Statil. J Pharm Pharmacol 1987; 39: 1019- 21. [DOI:10.1111/j.2042-7158.1987.tb03151.x]
15. Krejčí A, Michal P, Jakubik J, Říčný J, Doležal V. Regulation of signal transduction at M2 muscarinic receptor. Physiol Res 2004; 53 1: 131-40.
16. Machha A, Achike FI, Mustafa AM, Mustafa MR. Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide 2007; 16: 442-7. [DOI:10.1016/j.niox.2007.04.001]
17. Mittmann C. Differential coupling of m-cholinoceptors to Gi/Go-proteins in failing human myocardium. J Mol Cell Cardiol 2003; 35: 1241-9. [DOI:10.1016/S0022-2828(03)00235-9]
18. Monroy CA, Mackie DI, Roman DL. A high throughput screen for RGS proteins using steady state monitoring of free phosphate formation. PLoS One 2013; 8: 62247. [DOI:10.1371/journal.pone.0062247]
19. O'Brien JB, Wilkinson JC, Roman DL. Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials. J Biol Chem 2019; 294: 18571-85. [DOI:10.1074/jbc.REV119.007060]
20. Owen VJ, Burton PB, Mullen AJ, Birks EJ, Barton P, Yacoub MH. Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end-stage heart failure. Eur Heart J 2001; 22: 1015-20. [DOI:10.1053/euhj.2000.2578]
21. Senese NB, Kandasamy R, Kochan KE, Traynor JR. Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management. Front Mol Neurosci 2020; 13: 5. [DOI:10.3389/fnmol.2020.00005]
22. Shaw VS, Mohammadiarani H, Vashisth H, Neubig RR. Differential Protein Dynamics of Regulators of G-Protein Signaling: Role in Specificity of Small-Molecule Inhibitors. J Am Chem Soc 2018; 140: 3454-60. [DOI:10.1021/jacs.7b13778]
23. Siderovski DP, Kendall Harden T. The RGS protein superfamily. Handb Cell Signal 2003; 2: 631-638. [DOI:10.1016/B978-012124546-7/50586-6]
24. Tesmer JJ, Berman DM, Gilman AG, Sprang SR. Structure of RGS4 bound to AlF4-- activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell 1997; 89: 251-61. [DOI:10.1016/S0092-8674(00)80204-4]
25. Thackeray JT, Beanlands RS, Dasilva JN. Altered sympathetic nervous system signaling in the diabetic heart: emerging targets for molecular imaging. Am J Nucl Med Mol Imaging 2012; 2: 314.
26. Turner EM, Blazer LL, Neubig RR, Husbands SM. Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med Chem Lett 2012; 3: 146-50. [DOI:10.1021/ml200263y]
27. Vashisth H, Storaska AJ, Neubig RR, Brooks III CL. Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule. ACS Chem Biol 2013; 8: 2778-84. [DOI:10.1021/cb400568g]
28. Wald MR, Borda ES, Sterin-Borda L. Participation of nitric oxide and cyclic GMP in the supersensitivity of acute diabetic rat myocardium by cholinergic stimuli. Biochem Pharmacol 1998; 55: 1991-9. [DOI:10.1016/S0006-2952(98)00069-0]
29. Wang X, Adams LD, Pabon LM, Mahoney Jr WM, Beaudry D, Gunaje J, et al. RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy. J Mol Cell Cardiol 2008; 44: 539-50. [DOI:10.1016/j.yjmcc.2007.11.019]
30. Weber LP, Macleod KM. Influence of streptozotocin diabetes on the alpha-1 adrenoceptor and associated G proteins in rat arteries. J Pharmacol Exp Ther 1997; 283: 1469-78.
31. Zeydanli EN, Kandilci HB, Turan B. Doxycycline ameliorates vascular endothelial and contractile dysfunction in the thoracic aorta of diabetic rats. Cardiovasc Toxicol 2011; 11: 134-47. [DOI:10.1007/s12012-011-9107-1]

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