G Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure

Journal of the American Heart Association

Volumn 5, Issue 7, 2016, Pages

  Yang, Jian ^a   Villar, Van Anthony M ^b   Armando, Ines ^b   Jose, Pedro A ^b   Zeng, Chunyu ^a  

^a THIRD MILITARY MEDICAL UNIVERSITY   (China)

^b GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES   (United States)

Author keywords

blood pressure; G protein coupled receptor kinases; G protein coupled receptors; hypertension

Indexed keywords

G PROTEIN COUPLED RECEPTOR KINASE;

BLOOD PRESSURE; HUMAN; PHYSIOLOGY; SIGNAL TRANSDUCTION;

BLOOD PRESSURE; G-PROTEIN-COUPLED RECEPTOR KINASES; HUMANS; SIGNAL TRANSDUCTION;

EID: 85029713597     PISSN: None     EISSN: 20479980     Source Type: Journal    
DOI: 10.1161/JAHA.116.003519     Document Type: Article

References (117)

1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29– e322.
2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217– 223.
3. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, Hamza S, Speed J, Hall ME. Hypertension: physiology and pathophysiology. Compr Physiol. 2012;2:2393–2442.
4. Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing-implications in hypertension. J Mol Cell Cardiol. 2015;83:112–121.
5. Irannejad R, von Zastrow M. GPCR signaling along the endocytic pathway. Curr Opin Cell Biol. 2014;27:109–116.
6. Sato PY, Chuprun JK, Schwartz M, Koch WJ. The evolving impact of G protein-coupled receptor kinases in cardiac health and disease. Physiol Rev. 2015;95:377–404.
7. Brinks HL, Eckhart AD. Regulation of GPCR signaling in hypertension. Biochim Biophys Acta. 2010;1802:1268–1275.
8. Santulli G, Trimarco B, Iaccarino G. G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms. High Blood Press Cardiovasc Prev. 2013;20:5–12.
9. Oliver E, Rovira E, Monto F, Valldecabres C, Julve R, Muedra V, Ruiz N, Barettino D, D’Ocon P. beta-Adrenoceptor and GRK3 expression in human lymphocytes is related to blood pressure and urinary albumin excretion. J Hypertens. 2010;28:1281–1289.
10. Sanada H, Yoneda M, Yatabe J, Williams SM, Bartlett J, White MJ, Gordon LN, Felder RA, Eisner GM, Armando I, Jose PA. Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension
11. Vandell AG, Lobmeyer MT, Gawronski BE, Langaee TY, Gong Y, Gums JG, Beitelshees AL, Turner ST, Chapman AB, Cooper-DeHoff RM, Bailey KR, Boerwinkle E, Pepine CJ, Liggett SB, Johnson JA. G protein receptor kinase 4 polymorphisms: b-blocker pharmacogenetics and treatment-related outcomes in hypertension. Hypertension. 2012;60:957–964.
12. Collett JA, Hart AK, Patterson E, Kretzer J, Osborn JL. Renal angiotensin II type 1 receptor expression and associated hypertension in rats with minimal SHR nuclear genome. Physiol Rep. 2013;1:e00104.
13. 1 and angiotensin II type 1 receptors causes hypertension in old rats. Hypertension. 2012;59:1029–1036.
14. Pei F, Wang X, Yue R, Chen C, Huang J, Huang J, Li X, Zeng C. Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development. Mol Cell Biochem. 2015;402:1–8.
15. 1 dopamine receptor hyperphosphorylation in renal proximal tubules in hypertension. Kidney Int. 2006;70:1072–1079.
16. Felder RA, Sanada H, Xu J, Yu PY, Wang Z, Watanabe H, Asico LD, Wang W, Zheng S, Yamaguchi I, Williams SM, Gainer J, Brown NJ, Hazen-Martin D, Wong LJ, Robillard JE, Carey RM, Eisner GM, Jose PA. G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci USA. 2002;99:3872–3877.
17. Yang Z, Yu P, Asico LD, Felder RA, Jose PA. Protein phosphatase 2A B56alpha during development in the spontaneously hypertensive rat. Clin Exp Hypertens. 2004;26:243–254.
18. Harris RC. Abnormalities in renal dopamine signaling and hypertension: the role of GRK4. Curr Opin Nephrol Hypertens. 2012;21:61–65.
19. Small KM, Tanguay DA, Nandabalan K, Zhan P, Stephens JC, Liggett SB. Gene and protein domain-specific patterns of genetic variability within the G-protein coupled receptor superfamily. Am J Pharmacogenomics. 2003;3:65– 71.
20. Johnson LR, Robinson JD, Lester KN, Pitcher JA. Distinct structural features of G protein-coupled receptor kinase 5 (GRK5) regulate its nuclear localization and DNA-binding ability. PLoS One. 2013;8:e62508.
21. 1 receptor in hypertension. Hypertension. 2014;63:289–296.
22. Tutunea-Fatan E, Caetano FA, Gros R, Ferguson SS. GRK2 targeted knock-down results in spontaneous hypertension, and altered vascular GPCR signaling. J Biol Chem. 2015;290:5141–5155.
23. Keys JR, Zhou RH, Harris DM, Druckman CA, Eckhart AD. Vascular smooth muscle overexpression of G protein-coupled receptor kinase 5 elevates blood pressure, which segregates with sex and is dependent on Gi-mediated signaling. Circulation. 2005;112:1145–1153.
24. von Lueder TG, Gravning J, How OJ, Vinge LE, Ahmed MS, Krobert KA, Levy FO, Larsen TS, Smiseth OA, Aasum E, Attramadal H. Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload. Am J Physiol Heart Circ Physiol. 2012;303:H66–H74.
25. Sterne-Marr R, Leahey PA, Bresee JE, Dickson HM, Ho W, Ragusa MJ, Donnelly RM, Amie SM, Krywy JA, Brookins-Danz ED, Orakwue SC, Carr MJ, Yoshino-Koh K, Li Q, Tesmer JJ. GRK2 activation by receptors: role of the kinase large lobe and carboxyl-terminal tail. Biochemistry. 2009;48:4285– 4293.
26. Schmid E, Neef S, Berlin C, Tomasovic A, Kahlert K, Nordbeck P, Deiss K, Denzinger S, Herrmann S, Wettwer E, Weidendorfer M, Becker D, Sch€afer F, Wagner N, Erg€un S, Schmitt JP, Katus HA, Weidemann F, Ravens U, Maack C, Hein L, Ertl G, M€uller OJ, Maier LS, Lohse MJ, Lorenz K. Cardiac RKIP induces a beneficial b-adrenoceptor-dependent positive inotropy. Nat Med. 2015;21:1298–1306.
27. Chen M, Sato PY, Chuprun JK, Peroutka RJ, Otis NJ, Ibetti J, Pan S, Sheu SS, Gao E, Koch WJ. Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting. Circ Res. 2013;112:1121–1134.
28. Taguchi K, Matsumoto T, Kobayashi T. G-protein-coupled receptor kinase 2 and endothelial dysfunction: molecular insights and pathophysiological mechanisms. J Smooth Muscle Res. 2015;51:37–49.
29. 1 receptor-Gq/11alpha G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2. Am J Physiol Renal Physiol. 2007;293: F306–F315.
30. Sorriento D, Ciccarelli M, Santulli G, Illario M, Trimarco B, Iaccarino G. Trafficking GRK2: cellular and metabolic consequences of GRK2 subcellular localization. Transl Med UniSa. 2014;10:3–7.
31. Fusco A, Santulli G, Sorriento D, Cipolletta E, Garbi C, Dorn GW II, Trimarco B, Feliciello A, Iaccarino G. Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis. Cell Signal. 2012;24:468–475.
32. Sato PY, Chuprun JK, Ibetti J, Cannavo A, Drosatos K, Elrod JW, Koch WJ. GRK2 compromises cardiomyocyte mitochondrial function by diminishing fatty acid-mediated oxygen consumption and increasing superoxide levels. J Mol Cell Cardiol. 2015;89:360–364.
33. Avenda~no MS, Lucas E, Jurado-Pueyo M, Martınez-Revelles S, Vila-Bedmar R, Mayor F Jr, Salaices M, Briones AM, Murga C. Increased nitric oxide bioavailability in adult GRK2 hemizygous mice protects against angiotensin II-induced hypertension. Hypertension. 2014;63:369–375.
34. Eckhart AD, Ozaki T, Tevaearai H, Rockman HA, Koch WJ. Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure. Mol Pharmacol. 2002;61:749–758.
35. Cohn HI, Harris DM, Pesant S, Pfeiffer M, Zhou RH, Koch WJ, Dorn GW II, Eckhart AD. Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction. Am J Physiol Heart Circ Physiol. 2008;295:H1695–H1704.
36. Liu S, Premont RT, Kontos CD, Zhu S, Rockey DC. A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat Med. 2005;11:952–958.
37. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross J Jr, Lefkowitz RJ, Caron MG, Giros B. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci USA. 1996;93:12974–12979.
38. Wang Y, Gao E, Lau WB, Wang Y, Liu G, Li JJ, Wang X, Yuan Y, Koch WJ, Ma XL. G-protein-coupled receptor kinase 2-mediated desensitization of adiponectin receptor 1 in failing heart. Circulation. 2015;131:1392–1404.
39. Kim DH, Kim C, Ding EL, Townsend MK, Lipsitz LA. Adiponectin levels and the risk of hypertension: a systematic review and meta-analysis. Hypertension. 2013;62:27–32.
40. Du QH, Han L, Jiang JJ, Li PT, Wang XY, Jia X. Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats. World J Gastroenterol. 2013;19:2065–2072.
41. Vinge LE, Øie E, Andersson Y, Grøgaard HK, Andersen G, Attramadal H. Myocardial distribution and regulation of GRK and beta-arrestin isoforms in congestive heart failure in rats. Am J Physiol Heart Circ Physiol. 2001;281: H2490–H2499.
42. Ciccarelli M, Sorriento D, Franco A, Fusco A, Del Giudice C, Annunziata R, Cipolletta E, Monti MG, Dorn GW II, Trimarco B, Iaccarino G. Endothelial G protein-coupled receptor kinase 2 regulates vascular homeostasis through the control of free radical oxygen species. Arterioscler Thromb Vasc Biol. 2013;33:2415–2424.
43. Xing W, Li Y, Zhang H, Mi C, Hou Z, Quon MJ, Gao F. Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2013;305:H1111–H1119.
44. Cipolletta E, Campanile A, Santulli G, Sanzari E, Leosco D, Campiglia P, Trimarco B, Iaccarino G. The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance. Cardiovasc Res. 2009;84:407–415.
45. Passmore JC, Joshua IG, Rowell PP, Tyagi SC, Falcone JC. Reduced alpha adrenergic mediated contraction of renal preglomerular blood vessels as a function of gender and aging. J Cell Biochem. 2005;96:672–681.
46. Morris GE, Nelson CP, Standen NB, Challiss RA, Willets JM. Endothelin signalling in arterial smooth muscle is tightly regulated by G protein-coupled receptor kinase 2. Cardiovasc Res. 2010;85:424–433.
47. Inagaki S, Ghirlando R, Vishnivetskiy SA, Homan KT, White JF, Tesmer JJ, Gurevich VV, Grisshammer R. G protein-coupled receptor kinase 2 (GRK2) and 5 (GRK5) exhibit selective phosphorylation of the neurotensin receptor in vitro. Biochemistry. 2015;54:4320–4329.
48. Morris GE, Nelson CP, Everitt D, Brighton PJ, Standen NB, Challiss RA, Willets JM. G protein-coupled receptor kinase 2 and arrestin2 regulate arterial smooth muscle P2Y-purinoceptor signalling. Cardiovasc Res. 2011;89:193– 203.
49. Baines D. Kinases as targets for ENaC regulation. Curr Mol Pharmacol. 2013;6:50–64.
50. + channel by the RH domain of G protein-coupled receptor kinase, GRK2, and Galphaq/11. J Biol Chem. 2011;286:19259–19269.
51. Sanchez-Perez A, Kumar S, Cook DI. GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2. Biochem Biophys Res Commun. 2007;359:611–615.
52. + channels. Proc Natl Acad Sci USA. 2004;101:11886–11890.
53. 1 dopaminergic receptor differentially regulates desensitization and phosphorylation by G protein-coupled receptor kinase 2 and 3. Cell Signal. 2011;23:180–192.
54. 1 dopamine receptors by G protein-coupled receptor kinase 4. Kidney Int. 2002;62:790–798.
55. Trivedi M, Lokhandwala MF. Rosiglitazone restores renal D1A receptor-Gs protein coupling by reducing receptor hyperphosphorylation in obese rats. Am J Physiol Renal Physiol. 2005;289:F298–F304.
56. 1 receptor signaling in the renal proximal tubules of Sprague-Dawley rats. Free Radic Biol Med. 2007;42:756–764.
57. 1 receptor in offspring. Free Radic Biol Med. 2014;76:242–250.
58. 2 receptors depends on coexpression of G-protein-coupled receptor kinases 2 or 5. Eur J Biochem. 1999;260:112–119.
59. Cuevas S, Villar VA, Jose PA, Armando I. Renal dopamine receptors, oxidative stress, and hypertension. Int J Mol Sci. 2013;14:17553–17572.
60. Gros R, Chorazyczewski J, Meek MD, Benovic JL, Ferguson SS, Feldman RD. G-Protein-coupled receptor kinase activity in hypertension: increased vascular and lymphocyte G-protein receptor kinase-2 protein expression. Hypertension. 2000;35:38–42.
61. Oliver E, Flacco N, Arce C, Ivorra MD, D’Ocon MP, Noguera MA. Changes in adrenoceptors and G-protein-coupled receptor kinase 2 in L-NAME-induced hypertension compared to spontaneous hypertension in rats. J Vasc Res. 2014;51:209–220.
62. Huang CJ, Slusher AL, Whitehurst M, Wells M, Mock JT, Maharaj A, Shibata Y. Acute aerobic exercise mediates G protein-coupled receptor kinase 2 expression in human PBMCs. Life Sci. 2015;135:87–91.
63. Izzo R, Cipolletta E, Ciccarelli M, Campanile A, Santulli G, Palumbo G, Vasta A, Formisano S, Trimarco B, Iaccarino G. Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients. Clin Transl Sci. 2008;1:215–220.
64. Cohn HI, Xi Y, Pesant S, Harris DM, Hyslop T, Falkner B, Eckhart AD. G protein-coupled receptor kinase 2 expression and activity are associated with blood pressure in black Americans. Hypertension. 2009;54:71–76.
65. Vinge LE, Andressen KW, Attramadal T, Andersen GØ, Ahmed MS, Peppel K, Koch WJ, Freedman NJ, Levy FO, Skomedal T, Osnes JB, Attramadal H. Substrate specificities of G protein-coupled receptor kinase-2 and-3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Mol Pharmacol. 2007;72:582–591.
66. Yi XP, Zhou J, Baker J, Wang X, Gerdes AM, Li F. Myocardial expression and redistribution of GRKs in hypertensive hypertrophy and failure. Anat Rec A Discov Mol Cell Evol Biol. 2005;282:13–23.
67. Vinge LE, von Lueder TG, Aasum E, Qvigstad E, Gravning JA, How OJ, Edvardsen T, Bjørnerheim R, Ahmed MS, Mikkelsen BW, Oie E, Attramadal T, Skomedal T, Smiseth OA, Koch WJ, Larsen TS, Attramadal H. Cardiac-restricted expression of the carboxyl-terminal fragment of GRK3 uncovers distinct functions of GRK3 in regulation of cardiac contractility and growth: GRK3 controls cardiac alpha1-adrenergic receptor responsiveness. J Biol Chem. 2008;283:10601–10610.
68. Eckhart AD, Duncan SJ, Penn RB, Benovic JL, Lefkowitz RJ, Koch WJ. Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Circ Res. 2000;86:43–50.
69. Manunta P, Ferrandi M, Cusi D, Ferrari P, Staessen J, Bianchi G. Personalized therapy of hypertension: the past and the future. Curr Hypertens Rep. 2016;18:24.
70. Hasenkamp S, Telgmann R, Staessen JA, Hagedorn C, D€ordelmann C, Bek M, Brand-Herrmann SM, Brand E. Characterization and functional analyses of the human G protein-coupled receptor kinase 4 gene promoter. Hypertension. 2008;52:737–746.
71. Yang J, Villar VA, Jones JE, Jose PA, Zeng C. G protein-coupled receptor kinase 4: role in hypertension. Hypertension. 2015;65:1148–1155.
72. Sanada H, Yatabe J, Midorikawa S, Katoh T, Hashimoto S, Watanabe T, Xu J, Luo Y, Wang X, Zeng C, Armando I, Felder RA, Jose PA. Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression. Hypertension. 2006;47:1131–1139.
73. Villar VA, Jones JE, Armando I, Palmes-Saloma C, Yu P, Pascua AM, Keever L, Arnaldo FB, Wang Z, Luo Y, Felder RA, Jose PA. G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor. J Biol Chem. 2009;284:21425–21434.
74. Zhang MZ, Harris RC. Antihypertensive mechanisms of intra-renal dopamine. Curr Opin Nephrol Hypertens. 2015;24:117–122.
75. Natarajan AR, Eisner GM, Armando I, Browning S, Pezzullo JC, Rhee L, Dajani M, Carey RM, Jose PA. The renin-angiotensin and renal dopaminergic systems interact in normotensive humans. J Am Soc Nephrol. 2016;27:265–279.
76. Wang Z, Armando I, Asico LD, Escano C, Wang X, Lu Q, Felder RA, Schnackenberg CG, Sibley DR, Eisner GM, Jose PA. The elevated blood pressure of human GRK4cA142V transgenic mice is not associated with increased ROS production. Am J Physiol Heart Circ Physiol. 2007;292: H2083–H2092.
77. Wang Z, Zeng C, Villar VA, Chen SY, Konkalmatt P, Wang X, Asico LD, Jones JE, Yang Y, Sanada H, Felder RA, Eisner GM, Weir MR, Armando I, Jose PA. Human GRK4c142V variant promotes angiotensin II type I receptor-mediated hypertension via renal histone deacetylase type 1 inhibition. Hypertension. 2016;67:325–334.
78. 1R) [abstract]. J Am Soc Nephrol. 2007;18:148A.
79. Bengra C, Mifflin TE, Khripin Y, Manunta P, Williams SM, Jose PA, Felder RA. Genotyping essential hypertension SNPs using a homogenous PCR method with universal energy transfer primers. Clin Chem. 2002;48:2131– 2140.
80. Speirs HJ, Katyk K, Kumar NN, Benjafield AV, Wang WY, Morris BJ. Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension. J Hypertens. 2004;22:931–936.
81. Wang Y, Li B, Zhao W, Liu P, Zhao Q, Chen S, Li H, Gu D. Association study of G protein-coupled receptor kinase 4 gene variants with essential hypertension in northern Han Chinese. Ann Hum Genet. 2006;70:778–783.
82. Gu D, Su S, Ge D, Chen S, Huang J, Li B, Chen R, Qiang B. Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese. Hypertension. 2006;47:1147–1154.
83. Kimura L, Angeli CB, Auricchio MT, Fernandes GR, Pereira AC, Vicente JP, Pereira TV, Mingroni-Netto RC. Multilocus family-based association analysis of seven candidate polymorphisms with essential hypertension in an African-derived semi-isolated Brazilian population. Int J Hypertens. 2012;2012:859219.
84. Carey RM, Schoeffel CD, Gildea JJ, Jones JE, McGrath HE, Gordon LN, Park MJ, Sobota RS, Underwood PC, Williams J, Sun B, Raby B, Lasky-Su J, Hopkins PN, Adler GK, Williams SM, Jose PA, Felder RA. Salt sensitivity of blood pressure is associated with polymorphisms in the sodium-bicarbonate cotransporter. Hypertension. 2012;60:1359–1366.
85. Sanada H, Yatabe J, Midorikawa S, Hashimoto S, Watanabe T, Moore JH, Ritchie MD, Williams SM, Pezzullo JC, Sasaki M, Eisner GM, Jose PA, Felder RA. Single-nucleotide polymorphisms for diagnosis of salt sensitive hypertension. Clin Chem. 2006;52:352–360.
86. Staessen JA, Kuznetsova T, Zhang H, Maillard M, Bochud M, Hasenkamp S, Westerkamp J, Richart T, Thijs L, Li X, Brand-Herrmann SM, Burnier M, Brand E. Blood pressure and renal sodium handling in relation to genetic variation in the DRD1 promoter and GRK4. Hypertension. 2008;51:1643–1650.
87. Rana BK, Insel PA, Payne SH, Abel K, Beutler E, Ziegler MG, Schork NJ, O’Connor DT. Population-based sample reveals gene-gender interactions in blood pressure in White Americans. Hypertension. 2007;49:96–106.
88. Komolov KE, Bhardwaj A, Benovic JL. Atomic structure of GRK5 reveals distinct structural features novel for G protein-coupled receptor kinases. J Biol Chem. 2015;290:20629–20647.
89. Hullmann JE, Grisanti LA, Makarewich CA, Gao E, Gold JI, Chuprun JK, Tilley DG, Houser SR, Koch WJ. GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity. Circ Res. 2014;115:976–985.
90. Harris DM, Cohn HI, Pesant S, Eckhart AD. GPCR signalling in hypertension: role of GRKs. Clin Sci (Lond). 2008;115:79–89.
91. Sorriento D, Santulli G, Fusco A, Anastasio A, Trimarco B, Iaccarino G. Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-kappaB-dependent hypertrophic gene expression. Hypertension. 2010;56:696–704.
92. Wang L, Shen M, Wang F, Ma L. GRK5 ablation contributes to insulin resistance. Biochem Biophys Res Commun. 2012;429:99–104.
93. Ishizaka N, Alexander RW, Laursen JB, Kai H, Fukui T, Oppermann M, Lefkowitz RJ, Lyons PR, Griendling KK. G protein-coupled receptor kinase 5 in cultured vascular smooth muscle cells and rat aorta. Regulation by angiotensin II and hypertension. J Biol Chem. 1997;272:32482–32488.
94. Monto F, Oliver E, Vicente D, Buendıa F, Rueda J, Ag€uero J, Almenar L, Valldecabres C, Rovira E, Muedra V, Noguera MA, Ivorra MD, D’Ocon P. b2-and b1-adrenoceptor expression exhibits a common regulatory pattern with GRK2 and GRK5 in human and animal models of cardiovascular diseases. J Cardiovasc Pharmacol. 2015;66:478–486.
95. Yi XP, Gerdes AM, Li F. Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart-failure-prone rats. Hypertension. 2002;39:1058–1063.
96. 1 R and GRK5 expression following exercise training in heart failure. Hypertension. 2012;60:354–361.
97. Oppermann M, Freedman NJ, Alexander RW, Lefkowitz RJ. Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. J Biol Chem. 1996;271:13266–13272.
98. Tiberi M, Nash SR, Bertrand L, Lefkowitz RJ, Caron MG. Differential regulation of dopamine D1A receptor responsiveness by various G protein-coupled receptor kinases. J Biol Chem. 1996;271:3771–3778.
99. Zhang Y, Matkovich SJ, Duan X, Gold JI, Koch WJ, Dorn GW II. Nuclear effects of G-protein receptor kinase 5 on histone deacetylase 5-regulated gene transcription in heart failure. Circ Heart Fail. 2011;4:659–668.
100. Lobmeyer MT, Wang L, Zineh I, Turner ST, Gums JG, Chapman AB, Cooper-DeHoff RM, Beitelshees AL, Bailey KR, Boerwinkle E, Pepine CJ, Johnson JA. Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients. Pharmacogenet Genomics. 2011;21:42–49.
101. Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SL, Dorn GW II. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med. 2008;14:510–517.
102. Lodowski DT, Tesmer VM, Benovic JL, Tesmer JJ. The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs. J Biol Chem. 2006;281:16785–16793.
103. Simon V, Robin MT, Legrand C, Cohen-Tannoudji J. Endogenous G protein-coupled receptor kinase 6 triggers homologous beta-adrenergic receptor desensitization in primary uterine smooth muscle cells. Endocrinology. 2003;144:3058–3066.
104. Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol. 2010;77:405–415.
105. Rajagopal K, Whalen EJ, Violin JD, Stiber JA, Rosenberg PB, Premont RT, Coffman TM, Rockman HA, Lefkowitz RJ. 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.
106. Aiyar N, Disa J, Dang K, Pronin AN, Benovic JL, Nambi P. Involvement of G protein-coupled receptor kinase-6 in desensitization of CGRP receptors. Eur J Pharmacol. 2000;403:1–7.
107. 1-like receptor-mediated inhibition of Cl/HCO3-exchanger activity in rat intestinal epithelial IEC-6 cells is regulated by G protein-coupled receptor kinase 6 (GRK 6). Cell Physiol Biochem. 2006;18:347–360.
108. Salyer S, Lesousky N, Weinman EJ, Clark BJ, Lederer ED, Khundmiri SJ. Dopamine regulation of Na+-K+-ATPase requires the PDZ-2 domain of sodium hydrogen regulatory factor-1 (NHERF-1) in opossum kidney cells. Am J Physiol Cell Physiol. 2011;300:C425–C434.
109. Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci USA. 2002;99:11470–11475.
110. Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT. Dopaminergic supersen-sitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron. 2003;38:291–303.
111. Xu J, Watanabe H, Felder RA, Jose PA. GRK6 in the kidney in human and rat genetic hypertension [abstract]. FASEB J. 2001;15:A774.
112. Kavelaars A, Vroon A, Raatgever RP, Fong AM, Premont RT, Patel DD, Lefkowitz RJ, Heijnen CJ. Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6. J Immunol. 2003;171:6128–6134.
113. Rayner B, Ramesar R. The importance of G protein-coupled receptor kinase 4 (GRK4) in pathogenesis of salt sensitivity, salt sensitive hypertension and response to antihypertensive treatment. Int J Mol Sci. 2015;16:5741–5749.
114. Sanada H, Yatabe J, Yatabe MS, Yokokawa H, Williams S, Bartlett J, Wang Z, Felder R, Jose PA. G Protein-coupled receptor type 4 gene variants and response to antihypertensive medication [abstract]. Circulation. 2009;120: S1087.
115. Bhatnagar V, O’Connor DT, Brophy VH, Schork NJ, Richard E, Salem RM, Nievergelt CM, Bakris GL, Middleton JP, Norris KC, Wright J, Hiremath L, Contreras G, Appel LJ, Lipkowitz MS; AASK Study Investigators. G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions. Am J Hypertens. 2009;22:332–338.
116. Muskalla AM, Suter PM, Saur M, Nowak A, Hersberger M, Krayenbuehl PA. G-protein receptor kinase 4 polymorphism and response to antihypertensive therapy. Clin Chem. 2014;60:1543–1548.
117. Oliver E, Martı D, Monto F, Flacco N, Moreno L, Barettino D, Ivorra MD, D’Ocon P. The impact of alpha1-adrenoceptors up-regulation accompanied by the impairment of beta-adrenergic vasodilatation in hypertension. J Pharmacol Exp Ther. 2009;328:982–990.