GRK2 and beta-arrestins in cardiovascular disease: Established and emerging possibilities for therapeutic targeting

Current Molecular Pharmacology

Volumn 5, Issue 3, 2012, Pages 317-326

  Harvey, Alicia N ^a   Nguyen, Kristy ^a   Lymperopoulos, Anastasios ^a  

^a NOVA SOUTHEASTERN UNIVERSITY   (United States)

Author keywords

adrenergic receptor; arrestin signaling; Adrenal gland; Angiotensin II type 1 receptor; Cardiovascular disease; Catecholamine; GRK2; Heptahelical receptor; Vascular smooth muscle

Indexed keywords

ADRENALIN; ALDOSTERONE; BETA ARRESTIN; BETA ARRESTIN 1; BETA ARRESTIN 2; CATECHOLAMINE; ENDOTHELIN; G PROTEIN COUPLED RECEPTOR KINASE 2; NORADRENALIN;

ADRENAL MEDULLA; ADRENERGIC STIMULATION; ADRENERGIC SYSTEM; APOPTOSIS; CARDIOVASCULAR DISEASE; CATECHOLAMINE RELEASE; DISEASE COURSE; DOWN REGULATION; GENE THERAPY; HEART FAILURE; HEART INFARCTION; HEART MUSCLE CONTRACTILITY; HEART VENTRICLE HYPERTROPHY; HUMAN; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SIGNAL TRANSDUCTION; THERAPY EFFECT; UPREGULATION; VASCULAR SMOOTH MUSCLE;

EID: 84874817594     PISSN: 18744672     EISSN: 18744702     Source Type: Journal    
DOI: 10.2174/1874467211205030001     Document Type: Review

References (78)

1. Lander, E.S.; Linton, L.M.; Birren, B.; Nusbaum, C.; Zody, M.C.; Baldwin, J.; Devon, K.; Dewar, K.; Doyle, M.; FitzHugh, W.; Funke, R.; Gage, D.; Harris, K.; Heaford, A.; Howland, J.; Kann, L.; Lehoczky, J.; LeVine, R.; McEwan, P.; McKernan, K.; Meldrim, J.; Mesirov, J.P.; Miranda, C.; Morris, W.; Naylor, J.; Raymond, C.; Rosetti, M.; Santos, R.;, Sheridan, A.; Sougnez, C.; Stange-Thomann, N.; Stojanovic, N.; Subramanian, A.; Wyman, D.; Rogers, J.; Sulston, J.; Ainscough, R.; Beck, S.; Bentley, D.; Burton, J.; Clee, C.; Carter, N.; Coulson, A.; Deadman, R.; Deloukas, P.; Dunham, A.; Dunham, I.; Durbin, R.; French, L.; Grafham, D.; Gregory, S.; Hubbard, T.; Humphray, S.; Hunt, A.; Jones, M.; Lloyd, C.; McMurray, A.; Matthews, L.; Mercer, S.; Milne, S.; Mullikin, J.C.; Mungall, A.; Plumb, R.; Ross, M.; Shownkeen, R.; Sims, S.; Waterston, R.H.; Wilson, R.K.; Hillier, L.W.; McPherson, J.D.; Marra, M.A.; Mardis, E.R.; Fulton, L.A.; Chinwalla, A.T.; Pepin, K.H.; Gish, W.R.; Chissoe, S.L.; Wendl, M.C.; Delehaunty, K.D.; Miner, T.L.; Delehaunty, A.; Kramer, J.B.; Cook, L.L.; Fulton, R.S.; Johnson, D.L.; Minx, P.J.; Clifton, S.W.; Hawkins, T.; Branscomb, E.; Predki, P.; Richardson, P.; Wenning, S.; Slezak, T.; Doggett, N.; Cheng, J.F.; Olsen, A.; Lucas, S.; Elkin, C.; Uberbacher, E.; Frazier, M.; Gibbs, R.A.; Muzny, D.M.; Scherer, S.E.; Bouck, J.B.; Sodergren, E.J.; Worley, K.C.; Rives, C.M.; Gorrell, J.H.; Metzker, M.L.; Naylor, S.L.; Kucherlapati, R.S.; Nelson, D.L.; Weinstock, G.M.; Sakaki, Y.; Fujiyama, A.; Hattori, M.; Yada, T.; Toyoda, A.; Itoh, T.; Kawagoe, C.; Watanabe, H.; Totoki, Y.; Taylor, T.; Weissenbach, J.; Heilig, R.; Saurin, W.; Artiguenave, F.; Brottier, P.; Bruls, T.; Pelletier, E.; Robert, C.; Wincker, P.; Smith, D.R.; Doucette-Stamm, L.; Rubenfield, M.; Weinstock, K.; Lee, H.M.; Dubois, J.; Rosenthal, A.; Platzer, M.; Nyakatura, G.; Taudien, S.; Rump, A.; Yang, H.; Yu, J.; Wang, J.; Huang, G.; Gu, J.; Hood, L.; Rowen, L.; Madan, A.; Qin, S.; Davis, R.W.; Federspiel, N.A.; Abola, A.P.; Proctor, M.J.; Myers, R.M.; Schmutz, J.; Dickson, M.; Grimwood, J.; Cox, D.R.; Olson, M.V.; Kaul, R.; Raymond, C.; Shimizu, N.; Kawasaki, K.; Minoshima, S.; Evans, G.A.; Athanasiou, M.; Schultz, R.; Roe, B.A.; Chen, F.; Pan, H.; Ramser, J.; Lehrach, H.; Reinhardt, R.; McCombie, W.R.; de la Bastide, M.; Dedhia, N.; Blöcker, H.; Hornischer, K.; Nordsiek, G.; Agarwala, R.; Aravind, L.; Bailey, J.A.; Bateman, A.; Batzoglou, S.; Birney, E.; Bork, P.; Brown, D.G.; Burge, C.B.; Cerutti, L.; Chen, H.C.; Church, D.; Clamp, M.; Copley, R.R.; Doerks, T.; Eddy, S.R.; Eichler, E.E.; Furey, T.S.; Galagan, J.; Gilbert, J.G.; Harmon, C.; Hayashizaki, Y.; Haussler, D.;, Hermjakob, H.; Hokamp, K.; Jang, W.; Johnson, L.S.; Jones, T.A.; Kasif, S.; Kaspryzk, A.; Kennedy, S.; Kent, W.J.; Kitts, P.; Koonin, E.V.; Korf, I.; Kulp, D.; Lancet, D.; Lowe, T.M.; McLysaght, A.; Mikkelsen, T.; Moran, J.V.; Mulder, N.; Pollara, V.J.; Ponting, C.P.; Schuler, G.; Schultz, J.; Slater, G.; Smit, A.F.; Stupka, E.; Szustakowski, J.; Thierry-Mieg, D.; Thierry-Mieg, J.; Wagner, L.; Wallis, J.; Wheeler, R.; Williams, A.; Wolf, Y.I.; Wolfe, K.H.; Yang, S.P.; Yeh, R.F.; Collins, F.; Guyer, M.S.; Peterson, J.; Felsenfeld, A.; Wetterstrand, K.A.; Patrinos, A.; Morgan, M.J.; de Jong, P.; Catanese, J.J.; Osoegawa, K.;, Shizuya, H.; Choi, S.; Chen Y.J.; International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature, 2001, 409, 860-921.
2. Venter, J.C.; Adams, M.D.; Myers, E.W.; Li, P.W.; Mural, R.J.; Sutton, G.G.; Smith, H.O.; Yandell, M.; Evans, C.A.; Holt, R.A.; Gocayne, J.D.; Amanatides, P.; Ballew, R.M.; Huson, D.H.; Wortman, J.R.; Zhang, Q.; Kodira, C.D.; Zheng, X.H.; Chen, L.; Skupski, M.; Subramanian, G.; Thomas, P.D.; Zhang, J.; Gabor Miklos, G.L.; Nelson, C.; Broder, S.; Clark, A.G.; Nadeau, J.; McKusick, V.A.; Zinder, N.; Levine, A.J.; Roberts, R.J.; Simon, M.; Slayman, C.; Hunkapiller, M.; Bolanos, R.; Delcher, A.; Dew, I.; Fasulo, D.; Flanigan, M.; Florea, L.; Halpern, A.; Hannenhalli, S.; Kravitz, S.; Levy, S.; Mobarry, C.; Reinert, K.; Remington, K.; Abu-Threideh, J.; Beasley, E.; Biddick, K.; Bonazzi, V.; Brandon, R.; Cargill, M.; Chandramouliswaran, I.; Charlab, R.; Chaturvedi, K.; Deng, Z.; Di Francesco, V.; Dunn, P.; Eilbeck, K.; Evangelista, C.; Gabrielian, A.E.; Gan, W.; Ge, W.; Gong, F.; Gu, Z.; Guan, P.; Heiman, T.J.; Higgins, M.E.; Ji, R.R.; Ke, Z.; Ketchum, K.A.; Lai, Z.; Lei, Y.; Li, Z.; Li, J.; Liang, Y.; Lin, X.; Lu, F.; Merkulov, G.V.; Milshina, N.; Moore, H.M.; Naik, A.K.; Narayan, V.A.; Neelam, B.; Nusskern, D.; Rusch, D.B.; Salzberg, S.; Shao, W.; Shue, B.; Sun, J.; Wang, Z.; Wang, A.; Wang, X.; Wang, J.; Wei, M.; Wides, R.; Xiao, C.; Yan, C.; Yao, A.; Ye, J.; Zhan, M.; Zhang, W.; Zhang, H.; Zhao, Q.; Zheng, L.; Zhong, F.; Zhong, W.; Zhu, S.; Zhao, S.; Gilbert, D.; Baumhueter, S.; Spier, G.; Carter, C.; Cravchik, A.; Woodage, T.; Ali, F.; An, H.; Awe, A.; Baldwin, D.; Baden, H.; Barnstead, M.; Barrow, I.; Beeson, K.; Busam, D.; Carver, A.; Center, A.; Cheng, M.L.; Curry, L.; Danaher, S.; Davenport, L.; Desilets, R.; Dietz, S.; Dodson, K.; Doup, L.; Ferriera, S.; Garg, N.; Gluecksmann, A.; Hart, B.; Haynes, J.; Haynes, C.; Heiner, C.; Hladun, S.; Hostin, D.; Houck, J.; Howland, T.; Ibegwam, C.; Johnson, J.; Kalush, F.; Kline, L.; Koduru, S.; Love, A.; Mann, F.; May, D.; McCawley, S.; McIntosh, T.; McMullen, I.; Moy, M.; Moy, L.; Murphy, B.; Nelson, K.; Pfannkoch, C.; Pratts, E.; Puri, V.; Qureshi, H.; Reardon, M.; Rodriguez, R.; Rogers, Y.H.; Romblad, D.; Ruhfel, B.; Scott, R.; Sitter, C.; Smallwood, M.; Stewart, E.; Strong, R.; Suh, E.; Thomas, R.; Tint, N.N.; Tse, S.; Vech, C.; Wang, G.; Wetter, J.; Williams, S.; Williams, M.; Windsor, S.; Winn-Deen, E.; Wolfe, K.; Zaver, J.; Zaveri, K.; Abril, J.F.; Guigó, R.; Campbell, M.J.; Sjolander, K.V.; Karlak, B.; Kejariwal, A.; Mi, H.; Lazareva, B.; Hatton, T.; Narechania, A.; Diemer, K.; Muruganujan, A.; Guo, N.; Sato, S.; Bafna, V.; Istrail, S.; Lippert, R.; Schwartz, R.; Walenz, B.; Yooseph, S.; Allen, D.; Basu, A.; Baxendale, J.; Blick, L.; Caminha, M.; Carnes-Stine, J.; Caulk, P.; Chiang, Y.H.; Coyne, M.; Dahlke, C.; Mays, A.; Dombroski, M.; Donnelly, M.; Ely, D.; Esparham, S.; Fosler, C.; Gire, H.; Glanowski, S.; Glasser, K.; Glodek, A.; Gorokhov, M.; Graham, K.; Gropman, B.; Harris, M.; Heil, J.; Henderson, S.; Hoover, J.; Jennings, D.; Jordan, C.; Jordan, J.; Kasha, J.; Kagan, L.; Kraft, C.; Levitsky, A.; Lewis, M.; Liu, X.; Lopez, J.; Ma, D.; Majoros, W.; McDaniel, J.; Murphy, S.; Newman, M.; Nguyen, T.; Nguyen, N.; Nodell, M.; Pan, S.; Peck, J.; Peterson, M.; Rowe, W.; Sanders, R.; Scott, J.;, Simpson, M.; Smith, T.; Sprague, A.; Stockwell, T.; Turner, R.; Venter, E.; Wang, M.; Wen, M.; Wu, D.; Wu, M.; Xia, A.; Zandieh, A.; Zhu, X. The sequence of the human genome. Science, 2001, 291, 1304-1351.
3. Flower, D.R. Modeling G-protein-coupled receptors for drug design. Biochem. Biophys. Acta, 1999, 1422, 207-234.
4. Ferguson S.S. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol. Rev., 2001, 53, 1-24.
5. Hata, J.A.; Koch, W.J. Phosphorylation of G protein-coupled receptors: GPCR kinases in heart disease. Mol. Interv., 2003, 3, 264-272.
6. Rockman H.A.; Koch, W.J.; Lefkowitz, R.J. Seven-transmembranespanning receptors and heart function. Nature, 2002, 415, 206-212.
7. Reiter, E.; Lefkowitz, R.J. GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling. Trends Endocrinol. Metab., 2006, 17, 159-265.
8. Luttrell, L.M.; Gesty-Palmer, D. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol. Rev., 2010, 62, 305-330.
9. Rajagopal, S.; Rajagopal, K.; Lefkowitz, R.J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov.,. 2010, 9, 373-386.
10. DeWire, S.M.; Ahn, S.; Lefkowitz, R.J.; Shenoy, S.K. Betaarrestins and cell signaling. Annu. Rev. Physiol., 2007, 69, 483-510.
11. Brodde, O.E. Beta-adrenoceptors in cardiac disease. Pharmacol. Ther., 1993, 60, 405-430.
12. Communal, C.; Singh, K.; Sawyer, D.B.; Colucci, W.S. Opposing effects of beta(1)-and beta(2)-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation, 1999, 100, 2210-2212.
13. Chesley, A.; Lundberg, M.S.; Asai, T.; Xiao, R.P.; Ohtani, S.; Lakatta, E.G.; Crow, M.T. The β2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3-kinase. Cir. Res., 2000, 87, 1172-1179.
14. Zhu, W.Z.; Zheng, M.; Koch, W.J.; Lefkowitz, R. J.; Kobilka, B.K.; Xiao, R.P. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc. Natl. Acad. Sci. USA, 2001, 98, 1607-1612.
15. Dorn, G.W. 2nd; Tepe, N.M.; Lorenz, J.N.; Koch, W.J.; Liggett, S.B. Low-and high-level transgenic expression of beta2-adrenergic receptors differentially affect cardiac hypertrophy and function in Galphaq-overexpressing mice. Proc. Natl. Acad. Sci. USA, 1999, 96, 6400-6405.
16. Liggett, S.B.; Tepe, N.M.; Lorenz, J.N.; Canning, A.M.; Jantz, T.D.; Mitarai, S.; Yatani, A.; Dorn, G.W. 2nd. Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation, 2000, 101, 1707-1714.
17. Bristow, M.R.; Ginsburg, R.; Umans, V.; Fowler, M.; Minobe, W.; Rasmussen, R.; Zera, P.; Menlove, R.; Shah, P.; Jamieson, S. Beta 1-and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor downregulation in heart failure. Circ. Res., 1986, 59, 297-309.
18. Bristow, M.R.; Ginsburg, R.; Minobe, W.; Cubicciotti, R.; Sageman, W.S.; Lurie, K.; Billingham, M.E.; Harrison, D.C.; Stinson, E.B. Decreased catecholamine sensitivity and beta-adrenegicreceptor density in failing human hearts. N. Engl. J. Med., 1982, 307, 205-211.
19. Nikolaev, V.O.; Moshkov, A.; Lyon, A.R.; Miragoli, M.; Novak, P.; Paur, H.; Lohse, M.J.; Korchev, Y.E.; Harding, S.E.; Gorelik, J. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science, 2010, 327, 1653-1657.
20. Cohn, J.N.; Levine, T.B.; Olivari, M.T.; Garberg, V.; Lura, D.; Francis, G.S.; Simon, A.B.; Rector, T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med., 1984, 311, 819-923.
21. Port, J.D.; Bristow, M.R. Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. J. Mol. Cell. Cardiol., 2001, 33, 887-905.
22. Bristow M.R. Beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000, 101, 558-569.
23. Packer, M.; Bristow, M.R.; Cohn, J.N.; Colucci, W.S.; Fowler, M.B.; Gilbert, E.M.; Shusterman, N.H. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N. Engl. J. Med., 1996, 334, 1349-1355.
24. Packer, M. The development of positive inotropic agents for chronic heart failure: how have we gone astray? J. Am. Coll. Cardiol., 1993, 22, 119A-126A.
25. Harris, C.A.; Chuang, T.T.; Scorer, C.A. Expression of GRK2 is increased in the left ventricles of cardiomyopathic hamsters. Basic Res. Cardiol., 2001, 96, 364-368.
26. Yi, X.P.; Gerdes, A.M.; Li, F. Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart-failure-prone rats. Hypertension, 2002, 39, 1058-1063.
27. Dzimiri, N.; Muiya, P.; Andres, E.; Al-Halees, Z. Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases. Eur. J. Pharmacol., 2004, 489, 167-177.
28. Ungerer, M.; Kessebohm, K.; Kronsbein, K.; Lohse, M.J.; Richardt, G. Activation of beta-adrenergic receptor kinase during myocardial ischemia. Circ. Res., 1996, 79, 455-460.
29. Choi, D.J.; Koch, W.J.; Hunter, J.J.; Rockman, H.A. Mechanism of beta-adrenergic receptor desensitization in cardiac hypertrophy is increased beta-adrenergic receptor kinase. J. Biol. Chem., 1997, 272, 17223-17229.
30. Gros, R.; Benovic, J.L.; Tan, C.M.; Feldman, R.D. G-proteincoupled receptor kinase activity is increased in hypertension. J. Clin. Invest., 1997, 99, 2087-2093.
31. Iaccarino, G.; Barbato, E.; Cipolletta, E.; De Amicis, V.; Margulies, K.B.; Leosco, D.; Trimarco, B.; Koch, W.J. Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure. Eur. Heart J., 2005, 26, 1752-1758.
32. Hata, J.A.; Williams, M.L.; Schroder, J.N.; Lima, B.; Keys, J.R.; Blaxall, B.C.; Petrofski, J.A.; Jakoi, A.; Milano, C.A.; Koch, W.J. Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading. J. Card. Fail., 2006, 12, 360-368.
33. Bonita, R.E.; Raake, P.W.; Otis, N.J.; Chuprun, J.K.; Spivack, T.; Dasgupta, A.; Whellan, D.J.; Mather, P.J.; Koch, W.J. Dynamic changes in lymphocyte GRK2 levels in cardiac transplant patients: a biomarker for left ventricular function. Clin. Transl. Sci., 2010, 3, 14-18.
34. Rengo, G.; Lymperopoulos, A.; Koch, W.J. Future g protein-coupled receptor targets for treatment of heart failure. Curr. Treat. Options Cardiovasc. Med., 2009, 11, 328-338.
35. Ungerer, M.; Böhm, M.; Elce, J.S.; Erdmann, E.; Lohse, M.J. Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation, 1993, 87, 454-463.
36. Koch, W.J.; Rockman, H.A.; Samama, P.; Hamilton, R.A.; Bond, R.A.; Milano, C.A.; Leftowitz, R.J. Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a βARK inhibitor. Science, 1995, 268, 1350-1353.
37. Rockman, H.A.; Choi, D.J.; Rahman, N.U.; Akhter, S.A.; Lefkowitz, R.J.; Koch, W.J. Receptor-specific in vivo desensitization by the g protein-coupled receptor kinase-5 in transgenic mice. Proc. Natl. Acad. Sci. USA, 1996, 93, 9954-9959.
38. Akhter, S.A.; Eckhart, A.D.; Rockman, H.A.; Shotwell, K.; Lefkowitz, R.J.; Koch, W.J. In vivo inhibition of elevated myocardial β-adrenergic receptor kinase activity in hybrid transgenic mice restores normal β-adrenergic signaling and function. Circulation, 1999, 100, 648-653.
39. Rockman, H.A.; Chien, K.R.; Choi, D.J.; Iaccarino, G.; Hunter, J.J.; Ross, J. Jr.; Lefkowitz, R.J.; Koch, W.J. Expression of a betaadrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc. Natl. Acad. Sci. USA, 1998, 95, 7000-7005.
40. Harding, V.B.; Jones, L.R.; Lefkowitz, R.J.; Koch, W.J.; Rockman, H.A. Cardiac βARK1 inhibition prolongs survival and augments β blocker therapy in a mouse model of severe heart failure. Proc. Natl. Acad. Sci. USA, 2001, 98, 5809-5814.
41. Freeman, K.; Lerman, I.; Kranias, E.G.; Bohlmeyer, T.; Bristow, M.R.; Lefkowitz, R.J.; Iaccarino, G.; Koch, W.J.; Leinwand, L.A. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J. Clin. Invest., 2001, 107, 967-974.
42. Jaber M.; Koch, W.J.; Rockman, H.; Smith, B.; Bond, R.A.; Sulik, K.K.; Ross, J. Jr.; Lefkowitz, R. J.; Caron, M. G.; Giros, B. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc. Natl. Acad. Sci. USA, 1996, 93, 12974-12979.
43. Rockman, H.A.; Choi, D.J.; Akhter, S.A.; Jaber, M.; Giros, B.; Lefkowitz, R.J.; Caron M.G.; Koch, W.J. Control of myocardial contractile function by the level of β-adrenergic receptor kinase 1 in gene-targeted mice. J. Biol. Chem., 1998, 273, 18180-18184.
44. Matkovich, S.J.; Diwan, A.; Klanke, J.L.; Hammer, D.J.; Marreez, Y.; Odley, A.M.; Brunskill, E.W.; Koch, W.J.; Schwartz, R.J.; Dorn, G.W. 2nd. Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and β-adrenergic signaling. Circ. Res., 2006, 99, 966-1003.
45. Raake, P.W.; Vinge, L.E.; Gao, E.; Boucher, M.; Rengo, G.; Chen, X.; DeGeorge, B.R. Jr; Matkovich, S.; Houser, S.R.; Most, P.; Eckhart, A.D.; Dorn, G.W. 2nd; Koch, W.J. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myo cardial infarction prevents heart failure. Circ. Res., 2008, 103, 413-422.
46. Floras, J.S. The "unsympathetic" nervous system of heart failure. Circulation, 2002, 105, 1753-1755.
47. Rengo, G.; Lymperopoulos, A.; Zincarelli, C.; Donniacuo, M.; Soltys, S.; Rabinowitz, J.E.; Koch, W.J. Myocardial adenoassociated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation, 2009, 119, 89-98.
48. Lymperopoulos, A.; Rengo, G.; Koch, W.J. Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation. Trends Mol. Med., 2007, 13, 503-511.
49. Brede, M.; Nagy, G.; Philipp, M.; Sorensen, J.B.; Lohse, M.J.; Hein, L. Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol. Endocrinol., 2003, 17, 1640-1646.
50. Philipp, M.; Hein, L. Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol. Ther., 2004, 101, 65-74.
51. Philipp, M.; Brede, M.; Hein, L. Physiological significance of alpha(2)-adrenergic receptor subtype diversity: one receptor is not enough. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2002, 283, R287-R295.
52. Jewell-Motz, E.A.; Liggett, S.B. G protein-coupled receptor kinase specificity for phosphorylation and desensitization of alpha2-adrenergic receptor subtypes. J. Biol. Chem., 1996, 271, 18082-18087.
53. Kurose, H.; Lefkowitz, R.J. Differential desensitization and phosphorylation of three cloned and transfected alpha 2-adrenergic receptor subtypes. J. Biol. Chem., 1994, 269, 10093-10099.
54. Lembo, P.M.; Ghahremani, M.H.; Albert, P.R. Receptor selectivity of the cloned opossum G protein-coupled receptor kinase 2 (GRK2) in intact opossum kidney cells: role in desensitization of endogenous alpha2C-adrenergic but not serotonin 1B receptors. Mol. Endocrinol., 1999, 13, 138-147.
55. DeGraff, J.L.; Gagnon, A.W.; Benovic, J.L.; Orsini, M.J. Role of arrestins in endocytosis and signaling of alpha2-adrenergic receptor subtypes. J. Biol. Chem., 1999, 274, 11253-11259.
56. DeGraff, J.L.; Gurevich, V.V.; Benovic, J.L. The third intracellular loop of alpha 2-adrenergic receptors determines subtype specificity of arrestin interaction. J. Biol. Chem., 2002, 277, 43247-43252.
57. Lymperopoulos, A.; Rengo, G.; Funakoshi, H.; Eckhart, A.D.; Koch, W.J. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat. Med., 2007, 13, 315-323.
58. Lymperopoulos, A.; Rengo, G.; Gao, E.; Ebert, S.N.; Dorn, G.W. 2nd.; Koch, W.J. Reduction of sympathetic activity via adrenaltargeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction. J. Biol. Chem., 2010, 285, 16378-16386.
59. Lymperopoulos, A.; Rengo, G.; Zincarelli, C.; Soltys, S.; Koch, W.J. Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity. Mol. Ther., 2008, 16, 302-307.
60. Rengo, G.; Leosco, D.; Zincarelli, C.; Marchese, M.; Corbi, G.; Liccardo, D.; Filippelli, A.; Ferrara, N.; Lisanti, M.P.; Koch, W.J.; Lymperopoulos, A. Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure. Am. J. Physiol. Heart Circ. Physiol., 2010, 298, H2032-H2038.
61. Xiang, Y.; Kobilka, B.K. Myocyte adrenoceptor signaling pathways. Science 2003, 300, 1530-1532.
62. Noma, T.; Lemaire, A.; Naga Prasad, S.V.; Barki-Harrington, L.; Tilley, D.G.; Chen, J.; Le Corvoisier, P.; Violin, J.D.; Wei, H.; Lefkowitz, R.J.; Rockman, H.A. Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J. Clin. Invest., 2007, 117, 2445-2458.
63. Seta, K.; Nanamori, M.; Modrall, J.G.; Neubig, R.R.; Sadoshima, J. AT1 receptor mutant lacking heterotrimeric G protein coupling activates the Src-Ras-ERK pathway without nuclear translocation of ERKs. J. Biol. Chem., 2002, 277, 9268-9277.
64. Zhai, P.; Yamamoto, M.; Galeotti, J.; Liu, J.; Masurekar, M.; Thaisz, J.; Irie, K.; Holle, E.; Yu, X.; Kupershmidt, S.; Roden D.M.; Wagner, T.; Yatani, A.; Vatner, D.E.; Vatner, S.F.; Sadoshima, J. Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice. J. Clin. Invest., 2005, 115, 3045-3056.
65. Holloway, A.C.; Qian, H.; Pipolo, L.; Ziogas, J.; Miura, S.; Karnik, S.; Southwell, B.R.; Lew, M.J.; Thomas, W.G. Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1A angiotensin receptors. Mol. Pharmacol., 2002, 61, 768-777.
66. Aplin, M.; Christensen, G.L.; Schneider, M.; Heydorn, A.; Gammeltoft, S.; Kjølbye, A.L.; Sheikh, S.P.; Hansen, J.L. Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes. Basic Clin. Pharmacol. Toxicol., 2007, 100, 296-301.
67. Rajagopal, K.; Whalen, E.J.; Violin, J.D.; Stiber, J.A.; Rosenberg, P.B.; Premont, R.T.; Coffman, T.M.; Rockman, H.A.; Lefkowitz, R.J. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc. Natl. Acad. Sci. USA, 2006, 103, 16284-16289.
68. Kim, J.; Ahn, S.; Ren, X.R.; Whalen, E.J.; Reiter, E.; Wei, H.; Lefkowitz, R.J. Functional antagonism of different G proteincoupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling. Proc. Natl. Acad. Sci. USA, 2005, 102, 1442-1447.
69. Weber, K.T. Aldosterone in congestive heart failure. N. Engl. J. Med., 2001 345, 1689-1697.
70. Connell, J. M.; Davies, E. The new biology of aldosterone. J. Endocrinol., 2005 186, 1-20.
71. Marney, A. M.; Brown, N. J. Aldosterone and end-organ damage. Clin. Sci. (Lond), 2007, 113, 267-278.
72. Ganguly, A.; Davis, J.S. Role of calcium and other mediators in aldosterone secretion from the adrenal glomerulosa cells. Pharmacol. Rev., 1994, 46, 417-447.
73. De Gasparo, M.; Catt, K.J.; Inagami, T.; Wright, J.W.; Unger, T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol. Rev., 2000, 52, 415-472.
74. Lymperopoulos, A.; Rengo, G.; Zincarelli, C.; Kim, J.; Soltys, S.; Koch, W.J. An adrenal beta-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo. Proc. Natl. Acad. Sci. USA, 2009, 106, 5825-5830.
75. Lymperopoulos, A.; Rengo, G.; Zincarelli, C.; Kim, J.; Koch, W.J. Adrenal Beta-arrestin 1 inhibition in vivo attenuates postmyocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels. J. Am. Coll. Cardiol., 2011, 57, 356-365.
76. Kim, J.; Zhang, L.; Peppel, K.; Wu, J.H.; Zidar, D.A.; Brian, L.; DeWire, S.M.; Exum, S.T.; Lefkowitz, R.J.; Freedman, N.J. Betaarrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ. Res., 2008, 103, 70-79.
77. Kim, J.; Ahn, S.; Rajagopal, K.; Lefkowitz, R.J. Independent betaarrestin2 and Gq/protein kinase Czeta pathways for ERK stimulated by angiotensin type 1A receptors in vascular smooth muscle cells converge on transactivation of the epidermal growth factor receptor. J. Biol. Chem., 2009, 284, 11953-11962.
78. Ahn, S.; Kim, J.; Hara, M.R.; Ren, X.R.; Lefkowitz, R.J. Betaarrestin-2 mediates anti-apoptotic signaling through regulation of BAD phosphorylation. J. Biol. Chem., 2009, 284, 8855-8865.