The roles of RGS proteins in cardiometabolic disease.

التفاصيل البيبلوغرافية
العنوان:	The roles of RGS proteins in cardiometabolic disease.
المؤلفون:	McNeill SM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Zhao P; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (CCeMMP), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
المصدر:	British journal of pharmacology [Br J Pharmacol] 2024 Jul; Vol. 181 (14), pp. 2319-2337. Date of Electronic Publication: 2023 Apr 19.
نوع المنشور:	Journal Article; Review
اللغة:	English
بيانات الدورية:	Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
أسماء مطبوعة:	Publication: London : Wiley Original Publication: London, Macmillian Journals Ltd.
مواضيع طبية MeSH:	RGS Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism, Humans ; Animals ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/drug therapy ; Metabolic Diseases/metabolism ; Metabolic Diseases/drug therapy ; Signal Transduction
مستخلص:	G protein-coupled receptors (GPCRs) are the most prominent receptors on the surface of the cell and play a central role in the regulation of cardiac and metabolic functions. GPCRs transmit extracellular stimuli to the interior of the cells by activating one or more heterotrimeric G proteins. The duration and intensity of G protein-mediated signalling are tightly controlled by a large array of intracellular mediators, including the regulator of G protein signalling (RGS) proteins. RGS proteins selectively promote the GTPase activity of a subset of Gα subunits, thus serving as negative regulators in a pathway-dependent manner. In the current review, we summarise the involvement of RGS proteins in cardiometabolic function with a focus on their tissue distribution, mechanisms of action and dysregulation under various disease conditions. We also discuss the potential therapeutic applications for targeting RGS proteins in treating cardiometabolic conditions and current progress in developing RGS modulators. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc. (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
References:	Abramow‐Newerly, M., Roy, A. A., Nunn, C., & Chidiac, P. (2006). RGS proteins have a signalling complex: Interactions between RGS proteins and GPCRs, effectors, and auxiliary proteins. Cellular Signalling, 18(5), 579–591. https://doi.org/10.1016/j.cellsig.2005.08.010. Adams, L. D., Geary, R. L., McManus, B., & Schwartz, S. M. (2000). A comparison of aorta and vena cava medial message expression by cDNA array analysis identifies a set of 68 consistently differentially expressed genes, all in aortic media. Circulation Research, 87(7), 623–631. https://doi.org/10.1161/01.res.87.7.623. Akhter, S. A., Luttrell, L. M., Rockman, H. A., Iaccarino, G., Lefkowitz, R. J., & Koch, W. J. (1998). Targeting the receptor‐Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science, 280(5363), 574–577. https://doi.org/10.1126/science.280.5363.574. Alexander, S. P., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Abbracchio, M. P., Alexander, W., Al‐hosaini, K., Bäck, M., Barnes, N. M., Bathgate, R., … Ye, R. D. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein‐coupled receptors. British Journal of Pharmacology, 178(S1), S27–S156. 10.1111/bph.15538. Alexander, S. P., Fabbro, D., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Koesling, D., Ostrom, R., Pyne, N. J., Pyne, S., Russwurm, M., Seifert, R., Stasch, J.‐P., van der Stelt, M., van der Vliet, A., Watts, V. & Wong, S. S. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes. British Journal of Pharmacology, 178(S1), S313‐S411. doi: https://doi.org/10.1111/bph.15542. Alexander, S. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Buneman, O. P., Cidlowski, J. A., Christopoulos, A., Davenport, A. P., Fabbro, D., Spedding, M., Striessnig, J., Davies, J. A., Ahlers‐Dannen, K. E., … Zolghadri, Y. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Other Protein Targets. British Journal of Pharmacology, 178(S1), S1–S26. https://doi.org/10.1111/bph.15537. Alexander, S. P., Mathie, A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Aldrich, R. W., Attali, B., Baggetta, A. M., Becirovic, E., Biel, M., Bill, R. M., Catterall, W. A., … Zhu, M. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels. British Journal of Pharmacology, 178(S1), S157–S245. https://doi.org/10.1111/bph.15539. Asli, A., Higazy‐Mreih, S., Avital‐Shacham, M., & Kosloff, M. (2021). Residue‐level determinants of RGS R4 subfamily GAP activity and specificity towards the Gi subfamily. Cellular and Molecular Life Sciences, 78(17–18), 6305–6318. https://doi.org/10.1007/s00018-021-03898-4. Aziz, Q., Li, Y., & Tinker, A. (2018). Potassium channels in the sinoatrial node and their role in heart rate control. Channels, 12(1), 356–366. https://doi.org/10.1080/19336950.2018.1532255. Bastin, G., Luu, L., Batchuluun, B., Mighiu, A., Beadman, S., Zhang, H., He, C., al Rijjal, D., Wheeler, M. B., & Heximer, S. P. (2021). RGS4‐deficiency alters intracellular calcium and PKA‐mediated control of insulin secretion in glucose‐stimulated beta islets. Biomedicine, 9(8), 1008. https://doi.org/10.3390/biomedicines9081008. 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. The Journal of Biological Chemistry, 280(14), 13383–13394. https://doi.org/10.1074/jbc.M410163200. Bernstein, L. S., Ramineni, S., Hague, C., Cladman, W., Chidiac, P., Levey, A. I., & Hepler, J. R. (2004). RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11α signaling. The Journal of Biological Chemistry, 279(20), 21248–21256. https://doi.org/10.1074/jbc.M312407200. Blaxall, B. C., Spang, R., Rockman, H. A., & Koch, W. J. (2003). Differential myocardial gene expression in the development and rescue of murine heart failure. Physiological Genomics, 15(2), 105–114. https://doi.org/10.1152/physiolgenomics.00087.2003. Blazer, L. L., Storaska, A. J., Jutkiewicz, E. M., Turner, E. M., Calcagno, M., Wade, S. M., Wang, Q., Huang, X. P., Traynor, J. R., Husbands, S. M., Morari, M., & Neubig, R. R. (2015). Selectivity and anti‐Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS Chemical Neuroscience, 6(6), 911–919. https://doi.org/10.1021/acschemneuro.5b00063. Blazer, L. L., Zhang, H., Casey, E. M., Husbands, S. M., & Neubig, R. R. (2011). A nanomolar‐potency small molecule inhibitor of regulator of G‐protein signaling proteins. Biochemistry, 50(15), 3181–3192. https://doi.org/10.1021/bi1019622. Bodle, C. R., Mackie, D. I., Hayes, M. P., Schamp, J. H., Miller, M. R., Henry, M. D., Doorn, J. A., Houtman, J. C. D., James, M. A., & Roman, D. L. (2017). Natural products discovered in a high‐throughput screen identified as inhibitors of RGS17 and as cytostatic and cytotoxic agents for lung and prostate cancer cell lines. Journal of Natural Products, 80(7), 1992–2000. https://doi.org/10.1021/acs.jnatprod.7b00112. Bunemann, M., & Hosey, M. M. (1998). Regulators of G protein signaling (RGS) proteins constitutively activate Gβγ‐gated potassium channels. The Journal of Biological Chemistry, 273(47), 31186–31190. https://doi.org/10.1074/jbc.273.47.31186. Calo, L. A., Davis, P. A., & Rossi, G. P. (2014). Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long‐term sequelae: Insights from Bartter's and Gitelman's syndromes, human models of endogenous angiotensin II signaling antagonism. Journal of Hypertension, 32(11), 2109–2119. https://doi.org/10.1097/HJH.0000000000000321. Carman, C. V., Parent, J. L., Day, P. W., Pronin, A. N., Sternweis, P. M., Wedegaertner, P. B., Gilman, A. G., Benovic, J. L., & Kozasa, T. (1999). Selective regulation of Gαq/11 by an RGS domain in the G protein‐coupled receptor kinase, GRK2. The Journal of Biological Chemistry, 274(48), 34483–34492. https://doi.org/10.1074/jbc.274.48.34483. Chakir, K., Depry, C., Dimaano, V. L., Zhu, W. Z., Vanderheyden, M., Bartunek, J., Abraham, T. P., Tomaselli, G. F., Liu, S. B., Xiang, Y. K., Zhang, M., Takimoto, E., Dulin, N., Xiao, R. P., Zhang, J., & Kass, D. A. (2011). Gαs‐biased β2‐adrenergic receptor signaling from restoring synchronous contraction in the failing heart. Science Translational Medicine, 3(100), 100ra188. https://doi.org/10.1126/scitranslmed.3001909. Chang, Y. P., Liu, X., Kim, J. D., Ikeda, M. A., Layton, M. R., Weder, A. B., Cooper, R. S., Kardia, S. L. R., Rao, D. C., Hunt, S. C., Luke, A., Boerwinkle, E., & Chakravarti, A. (2007). Multiple genes for essential‐hypertension susceptibility on chromosome 1q. American Journal of Human Genetics, 80(2), 253–264. https://doi.org/10.1086/510918. Chen, Z., Wells, C. D., Sternweis, P. C., & Sprang, S. R. (2001). Structure of the rgRGS domain of p115RhoGEF. Nature Structural Biology, 8(9), 805–809. https://doi.org/10.1038/nsb0901-805. Chidiac, P. (2016). RGS proteins destroy spare receptors: Effects of GPCR‐interacting proteins and signal deamplification on measurements of GPCR agonist potency. Methods, 92, 87–93. https://doi.org/10.1016/j.ymeth.2015.08.011. Chidiac, P., Sobiesiak, A. J., Lee, K. N., Gros, R., & Nguyen, C. H. (2014). The eIF2B‐interacting domain of RGS2 protects against GPCR agonist‐induced hypertrophy in neonatal rat cardiomyocytes. Cellular Signalling, 26(6), 1226–1234. https://doi.org/10.1016/j.cellsig.2014.02.006. Cho, H., Park, C., Hwang, I. Y., Han, S. B., Schimel, D., Despres, D., & Kehrl, J. H. (2008). Rgs5 targeting leads to chronic low blood pressure and a lean body habitus. Molecular and Cellular Biology, 28(8), 2590–2597. https://doi.org/10.1128/MCB.01889-07. Ciccarelli, M., Sorriento, D., Fiordelisi, A., Gambardella, J., Franco, A., Del Giudice, C., Sala, M., Monti, M. G., Bertamino, A., Campiglia, P., Oliveti, M., Poggio, P., Trinchese, G., Cavaliere, G., Cipolletta, E., Mollica, M. P., Bonaduce, D., Trimarco, B., & Iaccarino, G. (2020). Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure. ESC Heart Failure, 7(4), 1571–1584. https://doi.org/10.1002/ehf2.12706. Cifelli, C., Rose, R. A., Zhang, H., Voigtlaender‐Bolz, J., Bolz, S. S., Backx, P. H., & Heximer, S. P. (2008). RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circulation Research, 103(5), 527–535. https://doi.org/10.1161/CIRCRESAHA.108.180984. Cohn, J. N., Ferrari, R., Sharpe, N., & on behalf of an International Forum on Cardiac Remodeling. (2000). Cardiac remodeling—Concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Journal of the American College of Cardiology, 35(3), 569–582. https://doi.org/10.1016/s0735-1097(99)00630-0. Cunningham, M. L., Waldo, G. L., Hollinger, S., Hepler, J. R., & Harden, T. K. (2001). Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Gα11 signaling. The Journal of Biological Chemistry, 276(8), 5438–5444. https://doi.org/10.1074/jbc.M007699200. Dasgupta, S., Ghosh, T., Dhar, J., Bhuniya, A., Nandi, P., das, A., Saha, A., das, J., Guha, I., Banerjee, S., Chakravarti, M., Dasgupta, P. S., Alam, N., Chakrabarti, J., Majumdar, S., Chakrabarti, P., Storkus, W. J., Baral, R., & Bose, A. (2021). RGS5–TGFβ–Smad2/3 axis switches pro‐ to anti‐apoptotic signaling in tumor‐residing pericytes, assisting tumor growth. Cell Death and Differentiation, 28(11), 3052–3076. https://doi.org/10.1038/s41418-021-00801-3. Davydov, I. V., & Varshavsky, A. (2000). RGS4 is arginylated and degraded by the N‐end rule pathway in vitro. The Journal of Biological Chemistry, 275(30), 22931–22941. https://doi.org/10.1074/jbc.M001605200. de Lucia, C., Grisanti, L. A., Borghetti, G., Piedepalumbo, M., Ibetti, J., Lucchese, A. M., Barr, E. W., Roy, R., Okyere, A. D., Murphy, H. C., Gao, E., Rengo, G., Houser, S. R., Tilley, D. G., & Koch, W. J. (2022). G protein‐coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post‐ischemic heart failure. Cardiovascular Research, 118(1), 169–183. https://doi.org/10.1093/cvr/cvab044. De Vries, L., & Gist Farquhar, M. (1999). RGS proteins: More than just GAPs for heterotrimeric G proteins. Trends in Cell Biology, 9(4), 138–144. https://doi.org/10.1016/s0962-8924(99)01515-9. Demirel, E., Arnold, C., Garg, J., Jäger, M. A., Sticht, C., Li, R., Kuk, H., Wettschureck, N., Hecker, M., & Korff, T. (2021). RGS5 attenuates baseline activity of ERK1/2 and promotes growth arrest of vascular smooth muscle cells. Cell, 10(7), 1748. https://doi.org/10.3390/cells10071748. Deng, W., Wang, X., Xiao, J., Chen, K., Zhou, H., Shen, D., Li, H., & Tang, Q. (2012). Loss of regulator of G protein signaling 5 exacerbates obesity, hepatic steatosis, inflammation and insulin resistance. PLoS ONE, 7(1), e30256. https://doi.org/10.1371/journal.pone.0030256. Dong, H., Zhang, Y., Wang, J., Kim, D. S., Wu, H., Sjögren, B., Gao, W., Luttrell, L., & Wang, H. (2017). Regulator of G protein signaling 2 is a key regulator of pancreatic β‐cell mass and function. Cell Death & Disease, 8(5), e2821. https://doi.org/10.1038/cddis.2016.216. Doupnik, C. A., Davidson, N., Lester, H. A., & Kofuji, P. (1997). RGS proteins reconstitute the rapid gating kinetics of Gβγ‐activated inwardly rectifying K+ channels. Proceedings of the National Academy of Sciences of the United States of America, 94(19), 10461–10466. https://doi.org/10.1073/pnas.94.19.10461. Dowal, L., Elliott, J., Popov, S., Wilkie, T. M., & Scarlata, S. (2001). Determination of the contact energies between a regulator of G protein signaling and G protein subunits and phospholipase Cβ1. Biochemistry, 40(2), 414–421. https://doi.org/10.1021/bi001923+. Esposito, G., Rapacciuolo, A., Naga Prasad, S. V., Takaoka, H., Thomas, S. A., Koch, W. J., & Rockman, H. A. (2002). Genetic alterations that inhibit in vivo pressure‐overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation, 105(1), 85–92. https://doi.org/10.1161/hc0102.101365. Faruque, M. U., Chen, G., Doumatey, A., Huang, H., Zhou, J., Dunston, G. M., Rotimi, C. N., & Adeyemo, A. A. (2011). Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African–Americans. Journal of Hypertension, 29(10), 1906–1912. https://doi.org/10.1097/HJH.0b013e32834b000d. Feldman, A. M., Cates, A. E., Veazey, W. B., Hershberger, R. E., Bristow, M. R., Baughman, K. L., Baumgartner, W. A., & Van Dop, C. (1988). Increase of the 40,000‐mol wt pertussis toxin substrate (G protein) in the failing human heart. The Journal of Clinical Investigation, 82(1), 189–197. https://doi.org/10.1172/JCI113569. Filippov, A. K., Fernandez‐Fernandez, J. M., Marsh, S. J., Simon, J., Barnard, E. A., & Brown, D. A. (2004). Activation and inhibition of neuronal G protein‐gated inwardly rectifying K+ channels by P2Y nucleotide receptors. Molecular Pharmacology, 66(3), 468–477. https://doi.org/10.1124/mol.66.3. Fujita, S., Inanobe, A., Chachin, M., Aizawa, Y., & Kurachi, Y. (2000). A regulator of G protein signalling (RGS) protein confers agonist‐dependent relaxation gating to a G protein‐gated K+ channel. The Journal of Physiology, 526(Pt 2), 341–347. https://doi.org/10.1111/j.1469-7793.2000.00341.x. Fukuhara, S., Chikumi, H., & Gutkind, J. S. (2000). Leukemia‐associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G12 family to Rho. FEBS Letters, 485(2–3), 183–188. https://doi.org/10.1016/s0014-5793(00)02224-9. Ganss, R. (2015). Keeping the balance right: Regulator of G protein signaling 5 in vascular physiology and pathology. Progress in Molecular Biology and Translational Science, 133, 93–121. https://doi.org/10.1016/bs.pmbts.2015.02.003. Garcia‐Guerra, L., Nieto‐Vazquez, I., Vila‐Bedmar, R., Jurado‐Pueyo, M., Zalba, G., Díez, J., Murga, C., Fernández‐Veledo, S., Mayor, F. Jr., & Lorenzo, M. (2010). G protein‐coupled receptor kinase 2 plays a relevant role in insulin resistance and obesity. Diabetes, 59(10), 2407–2417. https://doi.org/10.2337/db10-0771. Ghil, S., McCoy, K. L., & Hepler, J. R. (2014). Regulator of G protein signaling 2 (RGS2) and RGS4 form distinct G protein‐dependent complexes with protease activated‐receptor 1 (PAR1) in live cells. PLoS ONE, 9(4), e95355. https://doi.org/10.1371/journal.pone.0095355. Gross, V., Tank, J., Obst, M., Plehm, R., Blumer, K. J., Diedrich, A., Jordan, J., & Luft, F. C. (2005). Autonomic nervous system and blood pressure regulation in RGS2‐deficient mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 288(5), R1134–R1142. https://doi.org/10.1152/ajpregu.00246.2004. Gurevich, V. V., & Gurevich, E. V. (2019). GPCR signaling regulation: The role of GRKs and arrestins. Frontiers in Pharmacology, 10, 125. https://doi.org/10.3389/fphar.2019.00125. Hahntow, I. N., Mairuhu, G., van Valkengoed, I. G., Baas, F., Alewijnse, A. E., Koopmans, R. P., & Michel, M. C. (2009). Are RGS2 gene polymorphisms associated with high blood pressure in an ethnicity‐ and gender‐specific manner? American Journal of Hypertension, 22(1), 80–86. https://doi.org/10.1038/ajh.2008.310. Harris, I. S., Treskov, I., Rowley, M. W., Heximer, S., Kaltenbronn, K., Finck, B. N., Gross, R. W., Kelly, D. P., Blumer, K. J., & Muslin, A. J. (2004). G‐protein signaling participates in the development of diabetic cardiomyopathy. Diabetes, 53(12), 3082–3090. https://doi.org/10.2337/diabetes.53.12.3082. Harvey, R. D., & Belevych, A. E. (2003). Muscarinic regulation of cardiac ion channels. British Journal of Pharmacology, 139(6), 1074–1084. https://doi.org/10.1038/sj.bjp.0705338. Hauser, A. S., Attwood, M. M., Rask‐Andersen, M., Schioth, H. B., & Gloriam, D. E. (2017). Trends in GPCR drug discovery: New agents, targets and indications. Nature Reviews. Drug Discovery, 16(12), 829–842. https://doi.org/10.1038/nrd.2017.178. Hayes, M. P., O'Brien, J. B., Crawford, R. A., Fowler, C. A., Yu, L., Doorn, J. A., & Roman, D. L. (2021). Fragment‐based nuclear magnetic resonance screen against a regulator of G protein signaling identifies a binding “hot spot”. Chembiochem, 22(9), 1609–1620. https://doi.org/10.1002/cbic.202000740. Heineke, J., & Molkentin, J. D. (2006). Regulation of cardiac hypertrophy by intracellular signalling pathways. Nature Reviews. Molecular Cell Biology, 7(8), 589–600. https://doi.org/10.1038/nrm1983. Hepler, J. R., Berman, D. M., Gilman, A. G., & Kozasa, T. (1997). RGS4 and GAIP are GTPase‐activating proteins for Gqα and block activation of phospholipase Cβ by γ‐thio‐GTP‐Gqα. Proceedings of the National Academy of Sciences of the United States of America, 94(2), 428–432. https://doi.org/10.1073/pnas.94.2.428. Heximer, S. P., Knutsen, R. H., Sun, X., Kaltenbronn, K. M., Rhee, M. H., Peng, N., Oliveira‐dos‐Santos, A., Penninger, J. M., Muslin, A. J., Steinberg, T. H., Wyss, J. M., Mecham, R. P., & Blumer, K. J. (2003). Hypertension and prolonged vasoconstrictor signaling in RGS2‐deficient mice. The Journal of Clinical Investigation, 111(4), 445–452. https://doi.org/10.1172/JCI15598. Heximer, S. P., Srinivasa, S. P., Bernstein, L. S., Bernard, J. L., Linder, M. E., Hepler, J. R., & Blumer, K. J. (1999). G protein selectivity is a determinant of RGS2 function. The Journal of Biological Chemistry, 274(48), 34253–34259. https://doi.org/10.1074/jbc.274.48.34253. Holobotovskyy, V., Manzur, M., Tare, M., Burchell, J., Bolitho, E., Viola, H., Hool, L. C., Arnolda, L. F., McKitrick, D. J., & Ganss, R. (2013). Regulator of G‐protein signaling 5 controls blood pressure homeostasis and vessel wall remodeling. Circulation Research, 112(5), 781–791. https://doi.org/10.1161/CIRCRESAHA.111.300142. Huang, C. L., Feng, S., & Hilgemann, D. W. (1998). Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature, 391(6669), 803–806. https://doi.org/10.1038/35882. Huang, J., Chen, L., Yao, Y., Tang, C., Ding, J., Fu, C., Li, H., & Ma, G. (2016). Pivotal role of regulator of G‐protein signaling 12 in pathological cardiac hypertrophy. Hypertension, 67(6), 1228–1236. https://doi.org/10.1161/HYPERTENSIONAHA.115.06877. Huang, J., Pashkov, V., Kurrasch, D. M., Yu, K., Gold, S. J., & Wilkie, T. M. (2006). Feeding and fasting controls liver expression of a regulator of G protein signaling (Rgs16) in periportal hepatocytes. Comparative Hepatology, 5, 8. https://doi.org/10.1186/1476-5926-5-8. Huang, X., Charbeneau, R. A., Fu, Y., Kaur, K., Gerin, I., MacDougald, O. A., & Neubig, R. R. (2008). Resistance to diet‐induced obesity and improved insulin sensitivity in mice with a regulator of G protein signaling‐insensitive G184S Gnai2 allele. Diabetes, 57(1), 77–85. https://doi.org/10.2337/db07-0599. Huang, Z. M., Gold, J. I., & Koch, W. J. (2011). G protein‐coupled receptor kinases in normal and failing myocardium. Frontiers in Bioscience (Landmark Edition), 16(8), 3047–3060. https://doi.org/10.2741/3898. Iankova, I., Chavey, C., Clapé, C., Colomer, C., Guérineau, N. C., Grillet, N., Brunet, J. F.̧., Annicotte, J. S., & Fajas, L. (2008). Regulator of G protein signaling‐4 controls fatty acid and glucose homeostasis. Endocrinology, 149(11), 5706–5712. https://doi.org/10.1210/en.2008-0717. Ingi, T., Krumins, A. M., Chidiac, P., Brothers, G. M., Chung, S., Snow, B. E., Barnes, C. A., Lanahan, A. A., Siderovski, D. P., Ross, E. M., Gilman, A. G., & Worley, P. F. (1998). Dynamic regulation of RGS2 suggests a novel mechanism in G‐protein signaling and neuronal plasticity. The Journal of Neuroscience, 18(18), 7178–7188. https://doi.org/10.1523/JNEUROSCI.18-18-07178.1998. Jaen, C., & Doupnik, C. A. (2006). RGS3 and RGS4 differentially associate with G protein‐coupled receptor‐Kir3 channel signaling complexes revealing two modes of RGS modulation. Precoupling and collision coupling. The Journal of Biological Chemistry, 281(45), 34549–34560. https://doi.org/10.1074/jbc.M603177200. Jin, Y., Zhong, H., Omnaas, J. R., Neubig, R. R., & Mosberg, H. I. (2004). Structure‐based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors. The Journal of Peptide Research, 63(2), 141–146. https://doi.org/10.1111/j.1399-3011.2003.00114.x. Johnson, E. N., Seasholtz, T. M., Waheed, A. A., Kreutz, B., Suzuki, N., Kozasa, T., Jones, T. L. Z., Brown, J. H., & Druey, K. M. (2003). RGS16 inhibits signalling through the Gα13–Rho axis. Nature Cell Biology, 5(12), 1095–1103. https://doi.org/10.1038/ncb1065. Karoussiotis, C., Marti‐Solano, M., Stepniewski, T. M., Symeonof, A., Selent, J., & Georgoussi, Z. (2020). A highly conserved δ‐opioid receptor region determines RGS4 interaction. The FEBS Journal, 287(4), 736–748. https://doi.org/10.1111/febs.15033. Kehat, I., Davis, J., Tiburcy, M., Accornero, F., Saba‐el‐Leil, M. K., Maillet, M., York, A. J., Lorenz, J. N., Zimmermann, W. H., Meloche, S., & Molkentin, J. D. (2011). Extracellular signal‐regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth. Circulation Research, 108(2), 176–183. https://doi.org/10.1161/CIRCRESAHA.110.231514. Klepac, K., Yang, J., Hildebrand, S., & Pfeifer, A. (2019). RGS2: A multifunctional signaling hub that balances brown adipose tissue function and differentiation. Molecular Metabolism, 30, 173–183. https://doi.org/10.1016/j.molmet.2019.09.015. Kovoor, A., Seyffarth, P., Ebert, J., Barghshoon, S., Chen, C. K., Schwarz, S., Axelrod, J. D., Cheyette, B. N. R., Simon, M. I., Lester, H. A., & Schwarz, J. (2005). D2 dopamine receptors colocalize regulator of G‐protein signaling 9‐2 (RGS9‐2) via the RGS9 DEP domain, and RGS9 knock‐out mice develop dyskinesias associated with dopamine pathways. The Journal of Neuroscience, 25(8), 2157–2165. https://doi.org/10.1523/JNEUROSCI.2840-04.2005. Lee, P. C., Sowa, M. E., Gygi, S. P., & Harper, J. W. (2011). Alternative ubiquitin activation/conjugation cascades interact with N‐end rule ubiquitin ligases to control degradation of RGS proteins. Molecular Cell, 43(3), 392–405. https://doi.org/10.1016/j.molcel.2011.05.034. Lei, Q., Jones, M. B., Talley, E. M., Garrison, J. C., & Bayliss, D. A. (2003). Molecular mechanisms mediating inhibition of G protein‐coupled inwardly‐rectifying K+ channels. Molecules and Cells, 15(1), 1–9. https://www.ncbi.nlm.nih.gov/pubmed/12661754. Levay, K., Cabrera, J. L., Satpaev, D. K., & Slepak, V. Z. (1999). Gβ5 prevents the RGS7‐Gαo interaction through binding to a distinct Gγ‐like domain found in RGS7 and other RGS proteins. Proceedings of the National Academy of Sciences of the United States of America, 96(5), 2503–2507. https://doi.org/10.1073/pnas.96.5.2503. Li, H., He, C., Feng, J., Zhang, Y., Tang, Q., Bian, Z., Bai, X., Zhou, H., Jiang, H., Heximer, S. P., Qin, M., Huang, H., Liu, P. P., & Huang, C. (2010). Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Proceedings of the National Academy of Sciences of the United States of America, 107(31), 13818–13823. https://doi.org/10.1073/pnas.1008397107. Li, Y., Tang, X. H., Li, X. H., Dai, H. J., Miao, R. J., Cai, J. J., Huang, Z. J., Chen, A. F., Xing, X. W., Lu, Y., & Yuan, H. (2016). Regulator of G protein signalling 14 attenuates cardiac remodelling through the MEK–ERK1/2 signalling pathway. Basic Research in Cardiology, 111(4), 47. https://doi.org/10.1007/s00395-016-0566-1. Liu, Y., & Vashisth, H. (2021). Allosteric pathways originating at cysteine residues in regulators of G‐protein signaling proteins. Biophysical Journal, 120(3), 517–526. https://doi.org/10.1016/j.bpj.2020.12.010. Liu, Z., Chatterjee, T. K., & Fisher, R. A. (2002). RGS6 interacts with SCG10 and promotes neuronal differentiation. Role of the G gamma subunit‐like (GGL) domain of RGS6. The Journal of Biological Chemistry, 277(40), 37832–37839. https://doi.org/10.1074/jbc.M205908200. Mahata, T., Sengar, A. S., Basak, M., das, K., Pramanick, A., Verma, S. K., Singh, P. K., Biswas, S., Sarkar, S., Saha, S., Chatterjee, S., das, M., Stewart, A., & Maity, B. (2021). Hepatic regulator of G protein signaling 6 (RGS6) drives non‐alcoholic fatty liver disease by promoting oxidative stress and ATM‐dependent cell death. Redox Biology, 46, 102105. https://doi.org/10.1016/j.redox.2021.102105. Masuho, I., Balaji, S., Muntean, B. S., Skamangas, N. K., Chavali, S., Tesmer, J. J. G., Babu, M. M., & Martemyanov, K. A. (2020). A global map of G protein signaling regulation by RGS proteins. Cell, 183(2), 503–521.e19. https://doi.org/10.1016/j.cell.2020.08.052. McNabb, H. J., Gonzalez, S., Muli, C. S., & Sjogren, B. (2020). N‐terminal targeting of regulator of G protein signaling protein 2 for F‐box only protein 44‐mediated proteasomal degradation. Molecular Pharmacology, 98(6), 677–685. https://doi.org/10.1124/molpharm.120.000061. Mehdiabadi, N. R., Boon Sim, C., Phipson, B., Kalathur, R. K. R., Sun, Y., Vivien, C. J., ter Huurne, M., Piers, A. T., Hudson, J. E., Oshlack, A., Weintraub, R. G., Konstantinov, I. E., Palpant, N. J., Elliott, D. A., & Porrello, E. R. (2022). Defining the fetal gene program at single‐cell resolution in pediatric dilated cardiomyopathy. Circulation, 146(14), 1105–1108. https://doi.org/10.1161/CIRCULATIONAHA.121.057763. Miao, R., Lu, Y., Xing, X., Li, Y., Huang, Z., Zhong, H., Huang, Y., Chen, A. F., Tang, X., Li, H., Cai, J., & Yuan, H. (2016). Regulator of G‐protein signaling 10 negatively regulates cardiac remodeling by blocking mitogen‐activated protein kinase–extracellular signal‐regulated protein kinase 1/2 signaling. Hypertension, 67(1), 86–98. https://doi.org/10.1161/HYPERTENSIONAHA.115.05957. Mittmann, C., Chung, C. H., Höppner, G., Michalek, C., Nose, M., Schüler, C., Schuh, A., Eschenhagen, T., Weil, J., Pieske, B., Hirt, S., & Wieland, T. (2002). Expression of ten RGS proteins in human myocardium: Functional characterization of an upregulation of RGS4 in heart failure. Cardiovascular Research, 55(4), 778–786. https://doi.org/10.1016/s0008-6363(02)00459-5. Mohammadi, M., Mohammadiarani, H., Shaw, V. S., Neubig, R. R., & Vashisth, H. (2019). Interplay of cysteine exposure and global protein dynamics in small‐molecule recognition by a regulator of G‐protein signaling protein. Proteins, 87(2), 146–156. https://doi.org/10.1002/prot.25642. Monroy, C. A., Mackie, D. I., & Roman, D. L. (2013). A high throughput screen for RGS proteins using steady state monitoring of free phosphate formation. PLoS ONE, 8(4), e62247. https://doi.org/10.1371/journal.pone.0062247. Natochin, M., & Artemyev, N. O. (1998). A single mutation Asp229 → Ser confers upon Gsα the ability to interact with regulators of G protein signaling. Biochemistry, 37(39), 13776–13780. https://doi.org/10.1021/bi981155a. Nguyen, C. H., Ming, H., Zhao, P., Hugendubler, L., Gros, R., Kimball, S. R., & Chidiac, P. (2009). Translational control by RGS2. The Journal of Cell Biology, 186(5), 755–765. https://doi.org/10.1083/jcb.200811058. Niemeyer, A., Rinne, A., & Kienitz, M. C. (2019). Receptor‐specific regulation of atrial GIRK channel activity by different Ca2+‐dependent PKC isoforms. Cellular Signalling, 64, 109418. https://doi.org/10.1016/j.cellsig.2019.109418. Nisancioglu, M. H., Mahoney, W. M. Jr., Kimmel, D. D., Schwartz, S. M., Betsholtz, C., & Genove, G. (2008). Generation and characterization of rgs5 mutant mice. Molecular and Cellular Biology, 28(7), 2324–2331. https://doi.org/10.1128/MCB.01252-07. Nunn, C., Zhao, P., Zou, M. X., Summers, K., Guglielmo, C. G., & Chidiac, P. (2011). Resistance to age‐related, normal body weight gain in RGS2 deficient mice. Cellular Signalling, 23(8), 1375–1386. https://doi.org/10.1016/j.cellsig.2011.03.020. Nunn, C., Zou, M. X., Sobiesiak, A. J., Roy, A. A., Kirshenbaum, L. A., & Chidiac, P. (2010). RGS2 inhibits β‐adrenergic receptor‐induced cardiomyocyte hypertrophy. Cellular Signalling, 22(8), 1231–1239. https://doi.org/10.1016/j.cellsig.2010.03.015. O'Brien, J. B., Wilkinson, J. C., & Roman, D. L. (2019). Regulator of G‐protein signaling (RGS) proteins as drug targets: Progress and future potentials. The Journal of Biological Chemistry, 294(49), 18571–18585. https://doi.org/10.1074/jbc.REV119.007060. Owen, V. J., Burton, P. B., Mullen, A. J., Birks, E. J., Barton, P., & Yacoub, M. H. (2001). Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end‐stage heart failure. European Heart Journal, 22(12), 1015–1020. https://doi.org/10.1053/euhj.2000.2578. Pallaki, P., Georganta, E. M., Serafimidis, I., Papakonstantinou, M. P., Papanikolaou, V., Koutloglou, S., Papadimitriou, E., Agalou, A., Tserga, A., Simeonof, A., Thomaidou, D., Gaitanou, M., & Georgoussi, Z. (2017). A novel regulatory role of RGS4 in STAT5B activation, neurite outgrowth and neuronal differentiation. Neuropharmacology, 117, 408–421. https://doi.org/10.1016/j.neuropharm.2017.02.012. Papakonstantinou, M. P., Karoussiotis, C., & Georgoussi, Z. (2015). RGS2 and RGS4 proteins: New modulators of the κ‐opioid receptor signaling. Cellular Signalling, 27(1), 104–114. https://doi.org/10.1016/j.cellsig.2014.09.023. Park, S. E., Kim, J. M., Seok, O. H., Cho, H., Wadas, B., Kim, S. Y., Varshavsky, A., & Hwang, C. S. (2015). Control of mammalian G protein signaling by N‐terminal acetylation and the N‐end rule pathway. Science, 347(6227), 1249–1252. https://doi.org/10.1126/science.aaa3844. Park‐Windhol, C., Zhang, P., Zhu, M., Su, J., Chaves, L. Jr., Maldonado, A. E., King, M. E., Rickey, L., Cullen, D., & Mende, U. (2012). Gq/11‐mediated signaling and hypertrophy in mice with cardiac‐specific transgenic expression of regulator of G‐protein signaling 2. PLoS ONE, 7(7), e40048. https://doi.org/10.1371/journal.pone.0040048. Pashkov, V., Huang, J., Parameswara, V. K., Kedzierski, W., Kurrasch, D. M., Tall, G. G., Esser, V., Gerard, R. D., Uyeda, K., Towle, H. C., & Wilkie, T. M. (2011). Regulator of G protein signaling (RGS16) inhibits hepatic fatty acid oxidation in a carbohydrate response element‐binding protein (ChREBP)‐dependent manner. The Journal of Biological Chemistry, 286(17), 15116–15125. https://doi.org/10.1074/jbc.M110.216234. Penela, P., Murga, C., Ribas, C., Lafarga, V., & Mayor, F. Jr. (2010). The complex G protein‐coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. British Journal of Pharmacology, 160(4), 821–832. https://doi.org/10.1111/j.1476-5381.2010.00727.x. Popov, S. G., Krishna, U. M., Falck, J. R., & Wilkie, T. M. (2000). Ca2+/calmodulin reverses phosphatidylinositol 3,4,5‐trisphosphate‐dependent inhibition of regulators of G protein‐signaling GTPase‐activating protein activity. The Journal of Biological Chemistry, 275(25), 18962–18968. https://doi.org/10.1074/jbc.M001128200. Posner, B. A., Gilman, A. G., & Harris, B. A. (1999). Regulators of G protein signaling 6 and 7. Purification of complexes with Gβ5 and assessment of their effects on G protein‐mediated signaling pathways. The Journal of Biological Chemistry, 274(43), 31087–31093. https://doi.org/10.1074/jbc.274.43.31087. Posokhova, E., Wydeven, N., Allen, K. L., Wickman, K., & Martemyanov, K. A. (2010). RGS6/Gβ5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate. Circulation Research, 107(11), 1350–1354. https://doi.org/10.1161/CIRCRESAHA.110.224212. Prakoso, D., Tate, M., Blasio, M. J., & Ritchie, R. H. (2021). Adeno‐associated viral (AAV) vector‐mediated therapeutics for diabetic cardiomyopathy—Current and future perspectives. Clinical Science (London, England), 135(11), 1369–1387. https://doi.org/10.1042/CS20210052. Riddle, E. L., Rana, B. K., Murthy, K. K., Rao, F., Eskin, E., O'Connor, D. T., & Insel, P. A. (2006). Polymorphisms and haplotypes of the regulator of G protein signaling‐2 gene in normotensives and hypertensives. Hypertension, 47(3), 415–420. https://doi.org/10.1161/01.HYP.0000200714.81990.61. Riddy, D. M., Delerive, P., Summers, R. J., Sexton, P. M., & Langmead, C. J. (2018). G protein‐coupled receptors targeting insulin resistance, obesity, and type 2 diabetes mellitus. Pharmacological Reviews, 70(1), 39–67. https://doi.org/10.1124/pr.117.014373. Roman, D. L., Blazer, L. L., Monroy, C. A., & Neubig, R. R. (2010). Allosteric inhibition of the regulator of G protein signaling–Gα protein–protein interaction by CCG‐4986. Molecular Pharmacology, 78(3), 360–365. https://doi.org/10.1124/mol.109.063388. Roman, D. L., Ota, S., & Neubig, R. R. (2009). Polyplexed flow cytometry protein interaction assay: A novel high‐throughput screening paradigm for RGS protein inhibitors. Journal of Biomolecular Screening, 14(6), 610–619. https://doi.org/10.1177/1087057109336590. Roof, R. A., Sobczyk‐Kojiro, K., Turbiak, A. J., Roman, D. L., Pogozheva, I. D., Blazer, L. L., Neubig, R. R., & Mosberg, H. I. (2008). Novel peptide ligands of RGS4 from a focused one‐bead, one‐compound library. Chemical Biology & Drug Design, 72(2), 111–119. https://doi.org/10.1111/j.1747-0285.2008.00687.x. Ross, E. M., & Wilkie, T. M. (2000). GTPase‐activating proteins for heterotrimeric G proteins: Regulators of G protein signaling (RGS) and RGS‐like proteins. Annual Review of Biochemistry, 69, 795–827. https://doi.org/10.1146/annurev.biochem.69.1.795. Roy, A. A., Baragli, A., Bernstein, L. S., Hepler, J. R., Hebert, T. E., & Chidiac, P. (2006). RGS2 interacts with Gs and adenylyl cyclase in living cells. Cellular Signalling, 18(3), 336–348. https://doi.org/10.1016/j.cellsig.2005.05.004. Ruiz de Azua, I., Scarselli, M., Rosemond, E., Gautam, D., Jou, W., Gavrilova, O., Ebert, P. J., Levitt, P., & Wess, J. (2010). RGS4 is a negative regulator of insulin release from pancreatic β‐cells in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 107(17), 7999–8004. https://doi.org/10.1073/pnas.1003655107. 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. The Journal of Biological Chemistry, 274(14), 9899–9904. https://doi.org/10.1074/jbc.274.14.9899. Salazar, N. C., Chen, J., & Rockman, H. A. (2007). Cardiac GPCRs: GPCR signaling in healthy and failing hearts. Biochimica et Biophysica Acta, 1768(4), 1006–1018. https://doi.org/10.1016/j.bbamem.2007.02.010. Scherer, S. L., Cain, M. D., Kanai, S. M., Kaltenbronn, K. M., & Blumer, K. J. (2017). Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit Gα13. The Journal of Biological Chemistry, 292(24), 9906–9918. https://doi.org/10.1074/jbc.M116.771923. Semplicini, A., Lenzini, L., Sartori, M., Papparella, I., Calò, L. A., Pagnin, E., Strapazzon, G., Benna, C., Costa, R., Avogaro, A., Ceolotto, G., & Pessina, A. C. (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. Journal of Hypertension, 24(6), 1115–1124. https://doi.org/10.1097/01.hjh.0000226202.80689.8f. Senarath, K., Kankanamge, D., Samaradivakara, S., Ratnayake, K., Tennakoon, M., & Karunarathne, A. (2018). Chapter five—Regulation of G protein βγ signaling. International Review of Cell and Molecular Biology, 339, 133–191. https://doi.org/10.1016/bs.ircmb.2018.02.008. Shi, C. S., Lee, S. B., Sinnarajah, S., Dessauer, C. W., Rhee, S. G., & Kehrl, J. H. (2001). Regulator of G‐protein signaling 3 (RGS3) inhibits Gβ1γ2‐induced inositol phosphate production, mitogen‐activated protein kinase activation, and Akt activation. The Journal of Biological Chemistry, 276(26), 24293–24300. https://doi.org/10.1074/jbc.M100089200. Sjogren, B. (2011). Regulator of G protein signaling proteins as drug targets: Current state and future possibilities. Advances in Pharmacology, 62, 315–347. https://doi.org/10.1016/B978-0-12-385952-5.00002-6. Sjogren, B. (2017). The evolution of regulators of G protein signalling proteins as drug targets—20 years in the making: IUPHAR review 21. British Journal of Pharmacology, 174(6), 427–437. https://doi.org/10.1111/bph.13716. Sjogren, B., Parra, S., Atkins, K. B., Karaj, B., & Neubig, R. R. (2016). Digoxin‐mediated upregulation of RGS2 protein protects against cardiac injury. The Journal of Pharmacology and Experimental Therapeutics, 357(2), 311–319. https://doi.org/10.1124/jpet.115.231571. Sjogren, B., Parra, S., Heath, L. J., Atkins, K. B., Xie, Z. J., & Neubig, R. R. (2012). Cardiotonic steroids stabilize regulator of G protein signaling 2 protein levels. Molecular Pharmacology, 82(3), 500–509. https://doi.org/10.1124/mol.112.079293. Sjogren, B., Swaney, S., & Neubig, R. R. (2015). FBXO44‐mediated degradation of RGS2 protein uniquely depends on a cullin 4B/DDB1 complex. PLoS ONE, 10(5), e0123581. https://doi.org/10.1371/journal.pone.0123581. Slepak, V. Z. (2009). Chapter 6 Structure, function, and localization of Gβ5–RGS complexes. Progress in Molecular Biology and Translational Science, 86, 157–203. https://doi.org/10.1016/S1877-1173(09)86006-7. Snow, B. E., Hall, R. A., Krumins, A. M., Brothers, G. M., Bouchard, D., Brothers, C. A., Chung, S., Mangion, J., Gilman, A. G., Lefkowitz, R. J., & Siderovski, D. P. (1998). GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD‐95/Dlg/ZO‐1) domain. The Journal of Biological Chemistry, 273(28), 17749–17755. https://doi.org/10.1074/jbc.273.28.17749. Snow, B. E., Krumins, A. M., Brothers, G. M., Lee, S. F., Wall, M. A., Chung, S., Mangion, J., Arya, S., Gilman, A. G., & Siderovski, D. P. (1998). A G protein γ subunit‐like domain shared between RGS11 and other RGS proteins specifies binding to Gβ5 subunits. Proceedings of the National Academy of Sciences of the United States of America, 95(22), 13307–13312. https://doi.org/10.1073/pnas.95.22.13307. Srinivasa, S. P., Bernstein, L. S., Blumer, K. J., & Linder, M. E. (1998). Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America, 95(10), 5584–5589. https://doi.org/10.1073/pnas.95.10.5584. Sriram, K., & Insel, P. A. (2018). G protein‐coupled receptors as targets for approved drugs: How many targets and how many drugs? Molecular Pharmacology, 93(4), 251–258. https://doi.org/10.1124/mol.117.111062. Stewart, A., Maity, B., Anderegg, S. P., Allamargot, C., Yang, J., & Fisher, R. A. (2015). Regulator of G protein signaling 6 is a critical mediator of both reward‐related behavioral and pathological responses to alcohol. Proceedings of the National Academy of Sciences, 112(7), E786–E795. https://doi.org/10.1073/pnas.1418795112. Storaska, A. J., Mei, J. P., Wu, M., Li, M., Wade, S. M., Blazer, L. L., Sjögren, B., Hopkins, C. R., Lindsley, C. W., Lin, Z., Babcock, J. J., McManus, O. B., & Neubig, R. R. (2013). Reversible inhibitors of regulators of G‐protein signaling identified in a high‐throughput cell‐based calcium signaling assay. Cellular Signalling, 25(12), 2848–2855. https://doi.org/10.1016/j.cellsig.2013.09.007. Sun, X., Kaltenbronn, K. M., Steinberg, T. H., & Blumer, K. J. (2005). RGS2 is a mediator of nitric oxide action on blood pressure and vasoconstrictor signaling. Molecular Pharmacology, 67(3), 631–639. https://doi.org/10.1124/mol.104.007724. Takimoto, E., Koitabashi, N., Hsu, S., Ketner, E. A., Zhang, M., Nagayama, T., Bedja, D., Gabrielson, K. L., Blanton, R., Siderovski, D. P., Mendelsohn, M. E., & Kass, D. A. (2009). Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. The Journal of Clinical Investigation, 119(2), 408–420. https://doi.org/10.1172/JCI35620. Tamirisa, P., Blumer, K. J., & Muslin, A. J. (1999). RGS4 inhibits G‐protein signaling in cardiomyocytes. Circulation, 99(3), 441–447. https://doi.org/10.1161/01.cir.99.3.441. Tesmer, J. J., Berman, D. M., Gilman, A. G., & Sprang, S. R. (1997). Structure of RGS4 bound to AlF4−‐activated Giα1: Stabilization of the transition state for GTP hydrolysis. Cell, 89(2), 251–261. https://doi.org/10.1016/s0092-8674(00)80204-4. Turner, E. M., Blazer, L. L., Neubig, R. R., & Husbands, S. M. (2012). Small molecule inhibitors of regulators of G protein signaling (RGS) proteins. ACS Medicinal Chemistry Letters, 3(2), 146–150. https://doi.org/10.1021/ml200263y. Varadi, K., Michelfelder, S., Korff, T., Hecker, M., Trepel, M., Katus, H. A., Kleinschmidt, J. A., & Müller, O. J. (2012). Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell‐directed gene transfer vectors. Gene Therapy, 19(8), 800–809. https://doi.org/10.1038/gt.2011.143. Vashisth, H., Storaska, A. J., Neubig, R. R., & Brooks, C. L. 3rd. (2013). Conformational dynamics of a regulator of G‐protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule. ACS Chemical Biology, 8(12), 2778–2784. https://doi.org/10.1021/cb400568g. Vatner, D. E., Zhang, J., Oydanich, M., Guers, J., Katsyuba, E., Yan, L., Sinclair, D., Auwerx, J., & Vatner, S. F. (2018). Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Aging Cell, 17(4), e12751. https://doi.org/10.1111/acel.12751. Villasenor, A., Wang, Z. V., Rivera, L. B., Ocal, O., Asterholm, I. W., Scherer, P. E., Brekken, R. A., Cleaver, O., & Wilkie, T. M. (2010). Rgs16 and Rgs8 in embryonic endocrine pancreas and mouse models of diabetes. Disease Models & Mechanisms, 3(9–10), 567–580. https://doi.org/10.1242/dmm.003210. Wang, C. J., & Chidiac, P. (2019). RGS2 promotes the translation of stress‐associated proteins ATF4 and CHOP via its eIF2B‐inhibitory domain. Cellular Signalling, 59, 163–170. https://doi.org/10.1016/j.cellsig.2019.02.007. Wang, Q., Henry, T. A. N., Pronin, A. N., Jang, G. F., Lubaczeuski, C., Crabb, J. W., Bernal‐Mizrachi, E., & Slepak, V. Z. (2020). The regulatory G protein signaling complex, Gβ5–R7, promotes glucose‐ and extracellular signal‐stimulated insulin secretion. The Journal of Biological Chemistry, 295(21), 7213–7223. https://doi.org/10.1074/jbc.RA119.011534. Wang, Y., Lee, Y., Zhang, J., & Young, K. H. (2008). Identification of peptides that inhibit regulator of G protein signaling 4 function. Pharmacology, 82(2), 97–104. https://doi.org/10.1159/000138387. Wieland, T., & Mittmann, C. (2003). Regulators of G‐protein signalling: Multifunctional proteins with impact on signalling in the cardiovascular system. Pharmacology & Therapeutics, 97(2), 95–115. https://doi.org/10.1016/s0163-7258(02)00326-1. Xiao, B., Zhang, Y., Niu, W. Q., Gao, P. J., & Zhu, D. L. (2009). Haplotype‐based association of regulator of G‐protein signaling 5 gene polymorphisms with essential hypertension and metabolic parameters in Chinese. Clinical Chemistry and Laboratory Medicine, 47(12), 1483–1488. https://doi.org/10.1515/CCLM.2009.344. Xie, K., Allen, K. L., Kourrich, S., Colon‐Saez, J., Thomas, M. J., Wickman, K., & Martemyanov, K. A. (2010). Gβ5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling. Nature Neuroscience, 13(6), 661–663. https://doi.org/10.1038/nn.2549. Xie, Y., Wolff, D. W., Wei, T., Wang, B., Deng, C., Kirui, J. K., Jiang, H., Qin, J., Abel, P. W., & Tu, Y. (2009). Breast cancer migration and invasion depend on proteasome degradation of regulator of G‐protein signaling 4. Cancer Research, 69(14), 5743–5751. https://doi.org/10.1158/0008-5472.CAN-08-3564. Yang, J., Huang, J., Maity, B., Gao, Z., Lorca, R. A., Gudmundsson, H., Li, J., Stewart, A., Swaminathan, P. D., Ibeawuchi, S. R., Shepherd, A., Chen, C. K., Kutschke, W., Mohler, P. J., Mohapatra, D. P., Anderson, M. E., & Fisher, R. A. (2010). RGS6, a modulator of parasympathetic activation in heart. Circulation Research, 107(11), 1345–1349. https://doi.org/10.1161/CIRCRESAHA.110.224220. Yang, J., Kamide, K., Kokubo, Y., Takiuchi, S., Tanaka, C., Banno, M., Miwa, Y., Yoshii, M., Horio, T., Okayama, A., Tomoike, H., Kawano, Y., & Miyata, T. (2005). Genetic variations of regulator of G‐protein signaling 2 in hypertensive patients and in the general population. Journal of Hypertension, 23(8), 1497–1505. https://doi.org/10.1097/01.hjh.0000174606.41651.ae. Yoon, S. Y., Woo, J., Park, J. O., Choi, E. J., Shin, H. S., Roh, D. H., & Kim, K. S. (2015). Intrathecal RGS4 inhibitor, CCG50014, reduces nociceptive responses and enhances opioid‐mediated analgesic effects in the mouse formalin test. Anesthesia and Analgesia, 120(3), 671–677. https://doi.org/10.1213/ANE.0000000000000607. Zeller, C. E., & Dohlman, H. G. (2007). Illuminating Gβ5 signaling. Molecular Pharmacology, 72(4), 810–811. https://doi.org/10.1124/mol.107.040055. 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. The Journal of Biological Chemistry, 281(9), 5811–5820. https://doi.org/10.1074/jbc.M507871200. Zhao, P., & Furness, S. G. B. (2019). The nature of efficacy at G protein‐coupled receptors. Biochemical Pharmacology, 170, 113647. https://doi.org/10.1016/j.bcp.2019.113647. Zou, M. X., Roy, A. A., Zhao, Q., Kirshenbaum, L. A., Karmazyn, M., & Chidiac, P. (2006). RGS2 is upregulated by and attenuates the hypertrophic effect of α1‐adrenergic activation in cultured ventricular myocytes. Cellular Signalling, 18(10), 1655–1663. https://doi.org/10.1016/j.cellsig.2006.01.012.
معلومات مُعتمدة:	FT200100218 Australian Research Council
فهرسة مساهمة:	Keywords: GPCR signalling; RGS proteins; cardiometabolic disease; drug design
المشرفين على المادة:	0 (RGS Proteins) 0 (Receptors, G-Protein-Coupled)
تواريخ الأحداث:	Date Created: 20230325 Date Completed: 20240619 Latest Revision: 20240619
رمز التحديث:	20240619
DOI:	10.1111/bph.16076
PMID:	36964984
قاعدة البيانات:	MEDLINE

View record at Wiley

Full Text Finder

الوصف
تدمد:	1476-5381
DOI:	10.1111/bph.16076