Abstract
G-protein receptor kinases (GRKs) are indispensable for terminating signaling of G-protein coupled receptors (GPCR) through receptor desensitization and downregulation. Increased neurohormone levels in heart failure and the adverse consequences of constant neurohormonal stimulation suggest an important protective role for mechanisms that desensitize neurohormone receptor responses. For that reason, GRK2, the first GRK identified in the heart, has been extensively studied in heart failure, cardiac hypertrophy, and myocardial infarction. However, our understanding of the roles of GRKs in general, and the differential effects of cardiac receptor phosphorylation by individual cardiac-expressed GRKs, have evolved considerably in the last few years. Here, recent developments are reviewed, with an emphasis on novel GRK functions and signaling pathways.
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References
Strasser RH, Sibley DR, Lefkowitz RJ (1986) A novel catecholamine-activated adenosine cyclic 3′,5′-phosphate independent pathway for beta-adrenergic receptor phosphorylation in wild-type and mutant S49 lymphoma cells: mechanism of homologous desensitization of adenylate cyclase. Biochemistry 25(6):1371–1377
Benovic JL, Strasser RH, Caron MG, Lefkowitz RJ (1986) Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor. Proc Natl Acad Sci USA 83(9):2797–2801
Benovic JL, Mayor F Jr., Staniszewski C, Lefkowitz RJ, Caron MG (1987) Purification and characterization of the beta-adrenergic receptor kinase. J Biol Chem 262(19):9026–9032
Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ (1989) Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science 246(4927):235–240
Premont RT, Inglese J, Lefkowitz RJ (1995) Protein kinases that phosphorylate activated G protein-coupled receptors. FASEB J 9(2):175–182
Kunapuli P, Benovic JL (1993) Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family. Proc Natl Acad Sci USA 90(12):5588–5592
Premont RT, Koch WJ, Inglese J, Lefkowitz RJ (1994) Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases. J Biol Chem 269(9):6832–6841
Carman CV, Parent JL, Day PW, Pronin AN, Sternweis PM, Wedegaertner PB et al (1999) Selective regulation of Gαq/11 by an RGS domain in the G protein-coupled receptor kinase, GRK2. J Biol Chem 274:34483–34492
Sallese M, Mariggio S, D’Urbano E, Iacovelli L, De Blasi A (2000) Selective regulation of Gq signaling by G protein-coupled receptor kinase 2: driect interaction of kinase N terminus with activated galphaq. Mol Pharmacol 57:826–831
Day PW, Carman CV, Sterene-Marr R, Benovic JL, Wedegaertner PB (2003) Differential interaction of GRK2 with members of the G alpha q family. Biochem 42:9176–9184
Manning BS, Shotwell K, Mao L, Rockman HA, Koch WJ (2000) Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy. Circulation 102(22):2751–2757
Rockman HA, Chien KR, Choi DJ, Iaccarino G, Hunter JJ, Ross J Jr et al (1998) Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci USA 95(12):7000–7005
Pronin AN, Carman CV, Benovic JL (1998) Structure–function analysis of G protein-coupled receptor kinase-5. J Biol Chem 273(47):31510–31518
Thiyagarajan MM, Stracquatanio RP, Pronin AN, Evanko JL, Wedegaertner PB (2004) A predicted amphipathic helix mediates plasma membrane localization of GRK5. J Biol Chem 279(17):17989–17995
Lyubarsky AL, Chen C, Simon MI, Pugh EN Jr (2000) Mice lacking G-protein receptor kinase 1 have profoundly slowed recovery of cone-driven retinal responses. J Neurosci 20(6):2209–2217
Liu P, Osawa S, Weiss ER (2005) M opsin phosphorylation in intact mammalian retinas. J Neurochem 93(1):135–144
Peppel K, Boekhoff I, McDonald P, Breer H, Caron MG, Lefkowitz RJ (1997) G protein-coupled receptor kinase 3 (GRK3) gene disruption leads to loss of odorant receptor desensitization. J Biol Chem 272(41):25425–25428
Walker JK, Gainetdinov RR, Feldman DS, McFawn PK, Caron MG, Lefkowitz RJ et al (2004) G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation. Am J Physiol Lung Cell Mol Physiol 286(2):L312–L319
Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD et al (2003) Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron 38(2):291–303
Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK et al (1996) Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci USA 93(23):12974–12979
Sefton M, Blanco MJ, Penela P, Mayor F, Nieto MA (2000) Expression of the G protein-coupled receptor kinase 2 during early mouse embryogenesis. Mech Dev 98(1–2):127–131
Matkovich SJ, Diwan A, Klanke JL, Hammer DJ, Marreez Y, Odley AM et al (2006) Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling. Circ Res 99(9):996–1003
Conway SJ, Kruzynska-Frejtag A, Kneer PL, Machnicki M, Koushik SV (2003) What cardiovascular defect does my prenatal mouse mutant have, and why? Genesis 35(1):1–21
Meloni AR, Fralish GB, Kelly P, Salahpour A, Chen JK, Wechsler-Reya RJ et al (2006) Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol 26(20):7550–7560
Pitcher JA, Freedman NJ, Lefkowitz RJ (1998) G protein-coupled receptor kinases. Annu Rev Biochem 67:653–692
Ferguson SS (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53(1):1–24
Bristow MR, Hershberger RE, Port JD, Gilbert EM, Sandoval A, Rasmussen R et al (1990) Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 82(2 Suppl):I12–I25
Bristow MR, Kantrowitz NE, Ginsburg R, Fowler MB (1985) Beta-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol 17(Suppl 2):41–52
Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ (1993) Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation 87(2):454–463
Ungerer M, Parruti G, Bohm M, Puzicha M, DeBlasi A, Erdmann E et al (1994) Expression of beta-arrestins and beta-adrenergic receptor kinases in the failing human heart. Circ Res 74(2):206–213
Gros R, Benovic JL, Tan CM, Feldman RD (1997) G-protein-coupled receptor kinase activity is increased in hypertension. J Clin Invest 99(9):2087–2093
Oyama N, Urasawa K, Kaneta S, Sakai H, Saito T, Takagi C et al (2006) Angiotensin converting enzyme inhibitors attenuated the expression of G-protein coupled receptor kinases in heart failure patients. Circ J 70(3):362–363
Hata JA, Williams ML, Schroder JN, Lima B, Keys JR, Blaxall BC et al (2006) Lymphocyte levels of GRK2 (ßARK1) mirror changes in the LVAD-supporting failing human heart: Lower GRK2 associated with improved ß-adrenergic signaling after mechanical unloading. J Card Fail 12(5):360–368
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM et al (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 334(21):1349–1355
Merit HF (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353(9169):2001–2007
Rockman HA, Choi DJ, Akhter SA, Jaber M, Giros B, Lefkowitz RJ et al (1998) Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice. J Biol Chem 273(29):18180–18184
Vinge LE, Raake PW, Koch WJ (2008) Gene therapy in heart failure. Circ Res 102(12):1458–1470
Harding VB, Jones LR, Lefkowitz RJ, Koch WJ, Rockman HA (2001) Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci USA 98(10):5809–5814
Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ et al (2001) Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest 107(8):967–974
White DC, Hata JA, Shah AS, Glower DD, Lefkowitz RJ, Koch WJ (2000) Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction. Proc Natl Acad Sci USA 97(10):5428–5433
Shah AS, hite DC, mani S, ypson AP, illy RE, ilson K et al (2001) In vivo ventricular gene delivery of a ß-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 103:1311–1316
Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JE et al (2009) Myocardial adeno-associated virus serotype 6-ßARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation 119:89–98
Williams ML, Hata JA, Schroder J, Rampersaud E, Petrofski J, Jakoi A et al (2004) Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts. Circulation 109(13):1590–1593
Eckhart AD, Koch WJ (2002) Expression of a beta-adrenergic receptor kinase inhibitor reverses dysfunction in failing cardiomyocytes. Molecular Therapy 5:74–79
Li Z, Laugwitz KL, Pinkernell K, Pragst I, Baumgartner C, Hoffmann E et al (2003) Effects of two gbetagamma-binding proteins—N-terminally truncated phosducin and beta-adrenergic receptor kinase C terminus (betaARKct)—in heart failure. Gene Therapy 10(16):1354–1361
Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X et al (2008) G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 103(4):413–422
Liggett SB, Tepe NM, Lorenz JN, Canning AM, Jantz TD, Mitarai S et al (2000) Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 101(14):1707–1714
Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ (2007) Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med 13(3):315–323
Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA et al (1995) Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science 268(5215):1350–1353
Rockman HA, Choi DJ, Rahman NU, Akhter SA, Lefkowitz RJ, Koch WJ (1996) Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice. Proc Natl Acad Sci USA 93(18):9954–9959
Levay K, Satpaev DK, Pronin AN, Benovic JL, Slepak VZ (1998) Localization of the sites for Ca2+-binding proteins on G protein-coupled receptor kinases. Biochem 37(39):13650–13659
Martini JS, Raake PW, Vinge LE, DeGeorge Jr BB, Chuprun JK, Harris DM et al (2008) Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc Natl Acad Sci USA 105(34):12457–12462
Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS et al (2008) A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure. Nat Med 14(5):510–517
Fauchier L, Pierre B, de Labriolle A, Babuty D (2007) Comparison of the beneficial effect of beta-blockers on mortality in patients with ischaemic or non-ischaemic systolic heart failure: a meta-analysis of randomised controlled trials. Eur J Heart Fail 9(11):1136–1139
Pronin AN, Satpaev DK, Slepak VZ, Benovic JL (1997) Regulation of G protein-coupled receptor kinases by calmodulin and localization of the calmodulin binding domain. J Biol Chem 272(29):18273–18280
Freeman JLR, De La Cruz EM, Pollard TD, Lefkowitz RJ, Pitcher JA (1998) Regulation of G-protein coupled receptor kinase 5 (GRK5) by actin. J Biol Chem 273:20653–20657
Sallese M, Lacovelli L, Cumashi A, Capobianco L, Cuomo L, De Blasi A (2000) Regulation of G protein-coupled receptor kinase subtypes by calcium sensor proteins. Biochim Biophys Acta 1498:112–121
Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJ (2003) Keeping G proteins at bay: A complex between G protein-coupled receptor kinase 2 and Gßγ. Science 300(5623):1256–1262
Lodowski DT, Tesmer VM, Benovic JL, Tesmer JJ (2006) The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs. J Biol Chem 281(24):16785–16793
Carman CV, Lisanti MP, Benovic JL (1999) Regulation of G protein-coupled receptor kinases by caveolin. J Biol Chem 274(13):8858–8864
Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308(5721):512–517
Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL et al (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci USA 98(5):2449–2454
McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT et al (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290(5496):1574–1577
Ahn S, Shenoy SK, Wei H, Lefkowitz RJ (2004) Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J Biol Chem 279(34):35518–35525
Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H et al (2005) Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling. Proc Natl Acad Sci USA 102(5):1442–1447
Noma T, Lemaire A, Naga Prasad SV, Barki-Harrington L, Tilley DG, Chen J et al (2007) β-arrestin-mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest 117(9):2445–2458
Daub H, Weiss FU, Wallasch C, Ullrich A (1996) Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379:557–560
Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C et al (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402:884–888
Fischer OM, Hart S, Gschwind A, Ullrich A (2003) EGFR signal transactivation in cancer cells. Biochem Soc Trans 31:1203–1208
Wisler JW, DeWire SM, Whalen EJ, Violin JD, Drake MT, Ahn S et al (2007) A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signaling. Proc Natl Acad Sci USA 104(42):16657–16662
Kim IM, Tilley DG, Chen J, Salazar NC, Violin JD, Rockman H (2008) ß-Blockers alprenolol and carvedilol stimulate ß-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci USA 105:14555–14560
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Dorn, G.W. GRK mythology: G-protein receptor kinases in cardiovascular disease. J Mol Med 87, 455–463 (2009). https://doi.org/10.1007/s00109-009-0450-7
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DOI: https://doi.org/10.1007/s00109-009-0450-7