Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Atypical Actions of G Protein-Coupled Receptor Kinases

  • Kurose, Hitoshi (Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University)
  • Received : 2011.09.08
  • Accepted : 2011.10.12
  • Published : 2011.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

G protein-coupled receptor kinases (GRKs) and ${\beta}$-arrestins have been known as regulators of G protein-coupled receptors. However, it has been recently reported that GRKs and ${\beta}$-arrestins mediate receptor-mediated cellular responses in a G proteinin-dependent manner. In this scheme, GRKs work as a mediator or a scaffold protein. Among 7 members of the GRK family (GRK1-GRK7), GRK2 is the most extensively studied in vitro and in vivo. GRK2 is involved in cellular migration, insulin signaling, and cardiovascular disease. GRK6 in concert with ${\beta}$-arrestin 2 mediates chemoattractant-stimulated chemotaxis of T and B lymphocytes. GRK5 shuttles between the cytosol and nucleus, and regulates the activities of transcription factors. GRK3 and GRK4 do not seem to have striking effects on cellular responses other than receptor regulation. GRK1 and GRK7 play specific roles in regulation of rhodopsin function. In this review, these newly discovered functions of GRKs are briefly described.

Keywords

References

  1. Aiyar, N., Disa, J., Dang, K., Pronin, A. N., Benovic, J. L. and Nambi, P. (2000) Involvement of G protein-coupled receptor kinase-6 in desensitization of CGRP receptors. Eur. J. Pharmacol. 403, 1-7. https://doi.org/10.1016/S0014-2999(00)00419-2
  2. Anis, Y., Leshem, O., Reuveni, H., Wexler, I., Ben Sasson, R., Yahalom, B., Laster, M., Raz, I., Ben Sasson, S., Shafrir, E. and Ziv, E. (2004) Antidiabetic effect of novel modulating peptides of G-protein- coupled kinase in experimental models of diabetes. Diabetologia 47, 1232-1244.
  3. Arawaka, S., Wada, M., Goto, S., Karube, H., Sakamoto, M., Ren, C. H., Koyama, S., Nagasawa, H., Kimura, H., Kawanami, T., Kurita, K., Tajima, K., Daimon, M., Baba, M., Kido, T., Saino, S., Goto, K., Asao, H., Kitanaka, C., Takashita, E., Hongo, S., Nakamura, T., Kayama, T., Suzuki, Y., Kobayashi, K., Katagiri, T., Kurokawa, K., Kurimura, M., Toyoshima, I., Niizato, K., Tsuchiya, K., Iwatsubo, T., Muramatsu, M., Matsumine, H. and Kato, T. (2006) The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease. J. Neurosci. 26, 9227-9238. https://doi.org/10.1523/JNEUROSCI.0341-06.2006
  4. Barthet, G., Carrat, G., Cassier, E., Barker, B., Gaven, F., Pillot, M., Framery, B., Pellissier, L. P., Augier, J., Kang, D. S., Claeysen, S., Reiter, E., Banères, J. L., Benovic, J. L., Marin, P., Bockaert, J. and Dumuis, A. (2009) $\beta$-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J. 28, 2706-2718. https://doi.org/10.1038/emboj.2009.215
  5. Belmonte, S. L. and Blaxall, B. C. (2011) G protein coupled receptor kinases as therapeutic targets in cardiovascular disease. Circ. Res. 109, 309-319. https://doi.org/10.1161/CIRCRESAHA.110.231233
  6. Benovic, J. L., Onorato, J., Lohse, M. J., Dohlman, H. G., Staniszewski, C., Caron, M. G. and Lefkowitz, R. J. (1990) Synthetic peptides of the hamster β2-adrenoceptor as substrates and inhibitors of the β-adrenoceptor kinase. Br. J. Clin. Pharmacol. 30, 3S-12S. https://doi.org/10.1111/j.1365-2125.1990.tb05462.x
  7. Brinks, H., Boucher, M., Gao, E., Chuprun, J. K., Pesant, S., Raake, P. W., Huang, Z. M., Wang, X., Qiu, G., Gumpert, A., Harris, D. M., Eckhart, A. D., Most, P. and Koch, W. J. (2010) Level of G proteincoupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms. Circ. Res. 107,1140-1149. https://doi.org/10.1161/CIRCRESAHA.110.221010
  8. Cadigan, K. M. and Liu, Y. I. (2006) Wnt signaling: complexity at the surface. J. Cell Sci. 119, 395-402. https://doi.org/10.1242/jcs.02826
  9. Cant, S. H. and Pitcher, J. A. (2005) G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent reorganization of the actin cytoskeleton. Mol. Biol. Cell 16, 3088-3099. https://doi.org/10.1091/mbc.E04-10-0877
  10. Carman, C. V., Parent, J. L., Day, P. W., Pronin, A. N., Sternweis, P. M., Wedegaertner, P. B., Gilman, A. G., Benovic, J. L. and Tohru Kozasa, T. (1999) Selective regulation of Gαq/11 by an RGS domain in the G Protein-coupled receptor kinase, GRK2. J. Biol. Chem. 274, 34483-34492. https://doi.org/10.1074/jbc.274.48.34483
  11. Chen, L. and Feany, M. B. (2005) $\alpha$-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci. 8, 657-663. https://doi.org/10.1038/nn1443
  12. Chen, M., Philipp, M., Wang, J., Premont, R. T., Garrison, T. R., Caron, M. G., Lefkowitz, R. J. and Chen, W. (2009) G protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J. Biol. Chem. 284, 35040-35048. https://doi.org/10.1074/jbc.M109.047456
  13. Chen, W., Ren, X. R., Nelson, C. D., Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F. and Lefkowitz, R. J. (2004) Activity-dependent internalization of smoothened mediated by $\beta$-arrestin 2 and GRK2. Science 306, 2257-2260. https://doi.org/10.1126/science.1104135
  14. Chen, X., Zhu, H., Yuan, M., Fu, J., Zhou, Y. and Ma, L. (2010) Gprotein- coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J. Biol. Chem. 285, 12823-12830. https://doi.org/10.1074/jbc.M109.094243
  15. Cheng, S., Li, L., He, S., Liu, J., Sun, Y., He, M., Grasing, K., Premont, R. T. and Suo, W. Z. (2010) GRK5 defi ciency accelerates $\beta$-amyloid accumulation in Tg2576 mice via impaired cholinergic activity. J. Biol. Chem. 285, 41541-41548. https://doi.org/10.1074/jbc.M110.170894
  16. Ciaccarelli, M., Chuprun, J. K., Rengo, G., Gao, E., Wei, Z., Peroutka, R. J., Gold, J. I., Gumpert, A., Chen, M., Otis, N. J., Dorn II, G. W., Trimarco, B., Iaccarino, G. and Koch, W. J. (2011) G proteincoupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia. Circulation 123, 1953-1962. https://doi.org/10.1161/CIRCULATIONAHA.110.988642
  17. Cipolletta, E., Campanile, A., Santulli, G., Sanzari, E., Leosco, D., Campiglia, P., Trimarco, B. and Guido Iaccarino, G. (2009) The G protein coupled receptor kinase 2 plays an essential role in betaadrenergic receptor-induced insulin resistance. Cardiovasc. Res. 84, 407-415. https://doi.org/10.1093/cvr/cvp252
  18. Claing, A., Perry, S. J., Achiriloaie, M., Walker, J. K., Albanesi, J. P., Lefkowitz, R. J. and Premont, R. T. (2000) Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. Proc. Natl. Acad. Sci. USA. 97, 1119-1124. https://doi.org/10.1073/pnas.97.3.1119
  19. Craig, L. A., Hong, N. S. and McDonald, R. J. (2011) Revisiting the cholinergic hypothesis in the development of Alzheimer's disease. Neurosci. Biobehav. Rev. 35, 1397-1409. https://doi.org/10.1016/j.neubiorev.2011.03.001
  20. Dawson, T. M. and Dawson, V. L. (2003) Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819-822. https://doi.org/10.1126/science.1087753
  21. Dorn, G. W., II. (2010) Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol. Rev. 90, 1013-1062. https://doi.org/10.1152/physrev.00001.2010
  22. Hoefen, R. J. and Berk, B. C. (2006) The multifunctional GIT family of proteins. J. Cell Science 119, 1469-1475. https://doi.org/10.1242/jcs.02925
  23. Eckhart, A. D., Duncan, S. J., Penn, R. B., Benovic, J. L., Lefkowitz, R. J. and Koch, W. J. (2000) Hybrid transgenic mice reveal in vivo specifi city of G protein-coupled receptor kinases in the heart. Circ. Res. 86: 43-50. https://doi.org/10.1161/01.RES.86.1.43
  24. Eichmann, T., Lorenz, K., Hoffmann, M., Brockmann, J., Krasel, C., Lohse, M. J. and Quitterer, U. (2003) The amino-terminal domain of G-protein-coupled receptor kinase 2 is a regulatory G${\beta}{\gamma}$ binding site. J. Biol. Chem. 278, 8052-8057. https://doi.org/10.1074/jbc.M204795200
  25. Fernandez, N., Gottardo, F. L., Alonso, M. N., Monczor, F., Shayo, C. and Davio, C. (2011) Roles of phosphorylation-dependent and -independent mechanisms in the regulation of histamine H2 receptor by G protein-coupled receptor kinase 2. J. Biol. Chem. 286, 28697-28706. https://doi.org/10.1074/jbc.M111.269613
  26. Fong, A. M., Premont, R. T., Richardson, R. M., Yu, Y. R. A., Lefkowitz, R. J. and Patel, D. D. (2002) Defective lymphocyte chemotaxis in $\beta$-arrestin2- and GRK6-defi cient mice. Proc. Natl. Acd. Sci. USA. 99, 7478-7483. https://doi.org/10.1073/pnas.112198299
  27. Frank, S. R. and Hansen, S. H. (2008) The PIX-GIT complex: a G protein signaling cassette in control of cell shape. Semin. Cell Dev. Biol. 19, 234-244. https://doi.org/10.1016/j.semcdb.2008.01.002
  28. Gainetdinov, R. R., Bohn, L. M., Walker, J. K., Laporte, S. A., Macrae, A. D., Caron, M. G., Lefkowitz, R. J. and Premont, R. T. (1999) Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-defi cient mice. Neuron 24, 1029-1036. https://doi.org/10.1016/S0896-6273(00)81048-X
  29. Gordon, J. W., Shaw, J. A. and Kirshenbaum, L. A. (2011) Multiple facets of NF-${\kappa}B$ in the heart: to be or not to NF-${\kappa}B$. Circ. Res. 108, 1122-1132. https://doi.org/10.1161/CIRCRESAHA.110.226928
  30. Hoefen, R. J. and Berk, B. C. (2006) The multifunctional GIT family of proteins. J. Cell Sci. 119, 1469-1475. https://doi.org/10.1242/jcs.02925
  31. Hughes, S. C. and Fehon, R. G. (2007) Understanding ERM proteins - the awesome power of genetics fi nally brought to bear. Curr. Opin. Cell Biol. 19, 51-56. https://doi.org/10.1016/j.ceb.2006.12.004
  32. Iino, M., Furugori, T., Mori, T., Moriyama, S., Fukuzawa, A. and Shibano, T. (2002) Rational design and evaluation of new lead compound structures for selective $\beta$ARK1 inhibitors. J. Med. Chem. 45, 2150-2159. https://doi.org/10.1021/jm010093a
  33. Jimenez-Sainz, M. C., Murga, C., Kavelaars, A., Jurado-Pueyo, M., Krakstad, B. F., Heijnen, C. J., Mayor, F. Jr. and Aragay, A. M. (2006) G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits. Mol. Biol. Cell 17, 25-31.
  34. Kahsai, A. W., Zhu, S. and Fenteany, G. (2010) G protein-coupled receptor kinase 2 activates radixin, regulating membrane protrusion and motility in epithelial cells. Biochim. Biophys. Acta. 1803, 300-310. https://doi.org/10.1016/j.bbamcr.2009.11.002
  35. Kawashima, S. and Yokoyama, M. (2004) Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 998-1005. https://doi.org/10.1161/01.ATV.0000125114.88079.96
  36. Koch, W. J., Rockman, H. A., Samama, P., Hamilton, R. A., Bond, R. A., Milano, C. A., Lefkowitz, R. J. (1999) Cardiac function in mice overexpressing the $\beta$-adrenergic receptor kinase or a $\beta$ARK inhibitor. Science 268, 1350-1353.
  37. Kurnik, D., Cunningham, A. J., Sofowora, G. G., Kohli, U., Li, C., Friedman, E. A., Muszkat, M., Menon, U. B., Wood, A. J. J. and Stein, M. (2009) GRK5 Gln41Leu polymorphism is not associated with sensitivity to $\beta$1-adrenergic blockade in humans. Pharmacogenomics 10, 1581-1587. https://doi.org/10.2217/pgs.09.92
  38. Liggett, S. B., Cresci, S., Kelly, R. J., Syed, F. M., Matkovich, S. J., Hahn, H. S., Diwan, A., Martini, J. S., Sparks, L., Parekh, R. R., Spertus, J. A., Koch, W. J., Kardia, S. L. R. and Dorn, II, G. W. (2008) A GRK5 polymorphism that inhibits $\beta$-adrenergic receptor signaling is protective in heart failure. Nature Med. 14, 510-517. https://doi.org/10.1038/nm1750
  39. Liu, J., Rasul, I., Sun, Y., Wu, G., Li, L., Premont, R. T. and Suo, W. Z. (2009) GRK5 defi ciency leads to reduced hippocampal acetylcholine level via impaired presynaptic M2/M4 autoreceptor desensitization. J. Biol. Chem. 284, 19564-19571. https://doi.org/10.1074/jbc.M109.005959
  40. Liu, S., Premont, R. T., Kontos, C. D., Zhu, S. and Rockey, D. C. (2005) A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat. Med. 11, 952-958. https://doi.org/10.1038/nm1289
  41. Martini, J. S., Raake, P., Vinge, L. E., DeGeorge, B. R. Jr., Chuprun J. K., Harris, D. M., Gao, E., Eckhart, A. D., Pitcher, J. A. and Koch, W. J. (2008) Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc. Natl. Acad. Sci. U S A. 105, 12457-12462. https://doi.org/10.1073/pnas.0803153105
  42. Mayor, F., Jr., Lucas, E., Jurado-Pueyo, M., Garcia-Guerra, L., Nieto- Vazquez, I., Vila-Bedmar, R., Fernández-Veledo, S. and Murga, C. (2011) G Protein-coupled receptor kinase 2 (GRK2): a novel modulator of insulin resistance. Arch. Physiol. Biochem. 117, 125-130. https://doi.org/10.3109/13813455.2011.584693
  43. Meloni, A. R., Fralish, G. B., Kelly, P., Salahpour, A., Chen, J. K., Wechsler-Reya, R. J., Lefkowitz, R. J. and Caron, M. G. (2006) Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol. Cell Biol. 26, 7550-7560. https://doi.org/10.1128/MCB.00546-06
  44. Molnar, C., Holguin, H., Mayor, F., Jr., Ruiz-Gomez, A. and de Celis, J. F. (2007) The G protein-coupled receptor regulatory kinase GPRK2 participates in Hedgehog signaling in Drosophila. Proc. Natl. Acad. Sci. USA. 104, 7963-7968. https://doi.org/10.1073/pnas.0702374104
  45. 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. and Rockman, H. A. (2007) $\beta$-Arrestin-mediated $\beta$1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J. Clin. Invest. 117, 2445-2458. https://doi.org/10.1172/JCI31901
  46. Pao, C. S., Barker, B. L. and Benovic, J. L. (2009) Role of the amino terminus of G protein-coupled receptor kinase 2 in receptor phosphorylation. Biochemistry 48, 7325-7333. https://doi.org/10.1021/bi900408g
  47. Parameswaran, N., Pao, C. S., Leonhard, K. S., Kang, D. S., Kratz, M., Ley, S. C. and Benovic, J. L. (2006) Arrestin-2 and G proteincoupled receptor kinase 5 interact with NF${\kappa}B1$ p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. J. Biol. Chem. 281, 34159-34170. https://doi.org/10.1074/jbc.M605376200
  48. Penela, P., Murga, C., Ribas, C., Lafarga, V. and Federico Mayor, F., Jr. (2010a) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br. J. Pharmacol. 160, 821-832. https://doi.org/10.1111/j.1476-5381.2010.00727.x
  49. Penela, P., Rivas, V., Salcedo, A. and Mayor, F., Jr. (2010b) G proteincoupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc. Natl. Acad. Sci. USA. 107, 1118-1123. https://doi.org/10.1073/pnas.0905778107
  50. Penela, P., Ribas, C., Aymerich, I., Eijkelkamp, N., Barreiro, O., Heijnen, C. J., Kavelaars, A., Sánchez-Madrid, F. and Mayor. F., Jr. (2008) G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J. 27, 1206-1218. https://doi.org/10.1038/emboj.2008.55
  51. Penela, P., Ribas, C. and Mayor, F., Jr. (2003) Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal. 15, 973-981. https://doi.org/10.1016/S0898-6568(03)00099-8
  52. Premont, R. T. and Gainetdinov, R. R. (2007) Physiological roles of G protein-coupled receptor kinases and arrestins. Annu. Rev. Physiol. 69, 511-534. https://doi.org/10.1146/annurev.physiol.69.022405.154731
  53. Premont, R. T., Perry, S. J., Schmalzigaug, R., Roseman, J. T., Xing, Y. and Claing, A. (2004) The GIT/PIX complex: an oligomeric assembly of GIT family ARF GTPase-activating proteins and PIX family Rac1/Cdc42 guanine nucleotide exchange factors. Cell Signal. 16, 1001-1011. https://doi.org/10.1016/j.cellsig.2004.02.002
  54. Premont, R. T., Claing, A., Vitale, N., Freeman, J. L., Pitcher, J. A., Patton, W. A., Moss, J., Vaughan, M. and Lefkowitz, R. J. (1998) $\beta$2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc. Natl. Acad. Sci. USA. 95, 14082-14087. https://doi.org/10.1073/pnas.95.24.14082
  55. Pronin, A. N., Morris, A. J., Surguchov, A. and Benovic, J. L. (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J. Biol. Chem. 275, 26515-26522. https://doi.org/10.1074/jbc.M003542200
  56. Puca, R., Nardinocchi, L., Givol, D. and D'Orazi, G. (2010) Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells. Oncogene 29, 4378-4387. https://doi.org/10.1038/onc.2010.183
  57. Rockman, H. A., Koch, W. J. and Lefkowitz, R. J. (2002) Seven-transmembrane- spanning receptors and heart function. Nature 415, 206-212. https://doi.org/10.1038/415206a
  58. Rockman, H. A., Choi, D. J., Rahman, N. U., Akhter, S. A., Lefkowitz, R. J. and Koch, W. J. (1996) Receptor-specifi c in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice. Proc. Natl. Acad. Sci. USA. 93, 9954-9959. https://doi.org/10.1073/pnas.93.18.9954
  59. Scott, J. D. and Pawson, T. (2009) Cell signaling in space and time: where proteins come together and when they're apart. Science 326, 1220-1224. https://doi.org/10.1126/science.1175668
  60. Setyawan, J., Koide, K., Diller, T. C., Bunnage, M. E., Taylor, S. S., Nicolaou, K. C. and Brunton, L. L. (1999) Inhibition of protein kinases by balanol: specifi city within the serine/threonine protein kinase subfamily. Mol. Pharmacol. 56, 370-376.
  61. Sorriento, D., Ciccarelli, M., Santulli, G., Campanile, A., Altobelli, G. G., Cimini, V., Galasso, G., Astone, D., Piscione, F., Pastore, L., Trimarco, B. and Iaccarino, G. (2008) The G-protein-coupled receptor kinase 5 inhibits NF${\kappa}B$ transcriptional activity by inducing nuclear accumulation of $l{\kappa}B{\alpha}$. Proc. Natl. Acad. Sci. USA. 105, 17818-17823. https://doi.org/10.1073/pnas.0804446105
  62. Tarantino, P., De Marco, E. V., Annesi, G., Rocca, F. E., Annesi, F., Civitelli, D., Provenzano, G., Scornaienchi, V., Greco, V., Colica, C., Nicoletti, G. and Quattrone, A. (2011) Lack of association between G-protein coupled receptor kinase 5 gene and Parkinson's disease. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 156B, 104-107.
  63. Terry, A. V. Jr. and Buccafusco, J. J. (2003) The cholinergic hypothesis of age and Alzheimer's disease-related cognitive defi cits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther. 306, 821-827. https://doi.org/10.1124/jpet.102.041616
  64. Tesmer, J. J., Tesmer, V. M., Lodowski, D. T., Steinhagen, H. and Huber, J. (2010) Structure of human G protein-coupled receptor kinase 2 in complex with the kinase inhibitor balanol. J. Med. Chem. 53, 1867-1870. https://doi.org/10.1021/jm9017515
  65. Thal, D. M., Yeow, R. Y., Schoenau, C., Huber, J. and Tesmer, J. J. (2011) Molecular, mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Mol. Pharmacol. 80, 294-303. https://doi.org/10.1124/mol.111.071522
  66. Vazquez, A., Bond, E. E., Levine, A. J. and Bond, G. L. (2008) The genetics of the p53 pathway, apoptosis and cancer therapy. Nature Rev. Drug Discov. 7, 979-987. https://doi.org/10.1038/nrd2656
  67. Walker, J. K., Gainetdinov, R. R., Feldman, D. S., McFawn, P. K., Caron, M. G., Lefkowitz, R. J., Premont, R. T. and Fisher, J. T. (2004) G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation. Am. J. Physiol. Lung Cell Mol. Physiol. 286, L312-319. https://doi.org/10.1152/ajplung.00255.2003
  68. Whalen, E. J., Rajagopal, S. and Lefkowitz, R. J. (2011) Therapeutic potential of $\beta$-arrestin- and G protein-biased agonists. Tends. Mol. Med. 17, 126-139. https://doi.org/10.1016/j.molmed.2010.11.004
  69. Wilke, R. A., Reif, D. M. and Moore, J. H. (2005) Combinatorial pharmacogenetics. Nat. Rev. Drug Discov. 4, 911-918. https://doi.org/10.1038/nrd1874
  70. Willets, J. M., Challiss, R. A. J. and Nahorski, S. R. (2003) Non-visual GRKs: are we seeing the whole picture? Trends Pharmacol. Sci. 24, 626-633. https://doi.org/10.1016/j.tips.2003.10.003
  71. Winstel, R., Ihlenfeldt, H. G., Jung, G., Krasel, C. and Lohse, M. J. (2005) Peptide inhibitors of G protein-coupled receptor kinases. Biochem. Pharmacol. 70, 1001-1008. https://doi.org/10.1016/j.bcp.2005.06.015
  72. Zhang, P. and Mende, U. (2011) Regulators of G-protein signaling in the heart and their potential as therapeutic targets. Circ. Res. 109, 320-333. https://doi.org/10.1161/CIRCRESAHA.110.231423

Cited by

  1. Multiple functions of G protein-coupled receptor kinases vol.9, 2014, https://doi.org/10.1186/1750-2187-9-1
  2. Therapeutic Targets for Treatment of Heart Failure: Focus on GRKs and β-Arrestins Affecting βAR Signaling vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.01336
  3. GRK5 – A Functional Bridge Between Cardiovascular and Neurodegenerative Disorders vol.9, pp.None, 2011, https://doi.org/10.3389/fphar.2018.01484