Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GRK2 (G Protein-Coupled Receptor Kinase 2)

  • Arthur Hoi Hin Cheng
  • Hai-Ying Mary Cheng
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101765

Synonyms

Historical Background

G-protein coupled receptor kinase 2 (GRK2) was first discovered in 1989 by Benovic et al. as a 79.7 kDa protein that can specifically phosphorylate the agonist-occupied form of the β2-adrenergic receptor, hence the name β-adrenergic receptor kinase 1. Based on sequence homology and structural similarity, GRK2 is grouped with six other GRKs into a family of serine/threonine protein kinases that phosphorylate and regulate activated G-protein-coupled receptors (GPCRs). GRK2 has well-established roles in the cardiovascular system, nervous system, liver, and immune cells. Altered GRK2 expression has been reported in several disorders including heart failure, opioid addiction, multiple sclerosis, rheumatoid arthritis, major depression, schizophrenia, bipolar disorder, and Parkinson’s disease.

Structure, Expression, and Function

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References

  1. Aragay AM, Mellado M, Frade JM, Martin AM, Jimenez-Sainz MC, Martinez-A C, Mayor Jr F. Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2. Proc Natl Acad Sci USA. 1998;95:2985–90.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Arraes SMA, Freitas MS, da Silva SV, de Paula Neto HA, Alves-Filho JC, Auxiliadora Martins M, Basile-Filho A, Tavares-Murta BM, Barja-Fidalgo C, Cunha FQ. Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. Blood. 2006;108:2906–13.  https://doi.org/10.1182/blood-2006-05-024638.CrossRefPubMedGoogle Scholar
  3. Bailey CP, Oldfield S, Llorente J, Caunt CJ, Teschemacher AG, Roberts L, McArdle CA, Smith FL, Dewey WL, Kelly E, Henderson G. Involvement of PKC alpha and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of mu-opioid receptors in mature brain neurons. Br J Pharmacol. 2009;158:157–64.  https://doi.org/10.1111/j.1476-5381.2009.00140.x.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Benovic J, DeBlasi A, Stone W, Caron M, Lefkowitz R. Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science. 1989;246:235–40.  https://doi.org/10.1126/science.2552582.CrossRefPubMedGoogle Scholar
  5. Bezard E, Gross CE, Qin L, Gurevich VV, Benovic JL, Gurevich EV. L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain. Neurobiol Dis. 2005;18:323–35.  https://doi.org/10.1016/j.nbd.2004.10.005.CrossRefPubMedGoogle Scholar
  6. Brede M, Nagy G, Philipp M, Sorensen JB, Lohse MJ, Hein L. Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol. 2003;17:1640–6.  https://doi.org/10.1210/me.2003-0035.CrossRefPubMedGoogle Scholar
  7. Carman CV, Lisanti MP, Benovic JL. Regulation of G protein-coupled receptor kinases by caveolin. J Biol Chem. 1999;274:8858–64.  https://doi.org/10.1074/jbc.274.13.8858.CrossRefPubMedGoogle Scholar
  8. Chuang TT, Paolucci L, De Blasi A. Inhibition of G protein-coupled receptor kinase subtypes by Ca2+/calmodulin. J Biol Chem. 1996;271:28691–6.  https://doi.org/10.1074/jbc.271.45.28691.CrossRefPubMedGoogle Scholar
  9. 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;84:407–15.  https://doi.org/10.1093/cvr/cvp252.CrossRefPubMedGoogle Scholar
  10. 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;54:71–6.  https://doi.org/10.1161/HYPERTENSIONAHA.108.125955.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cong M, Perry SJ, Lin FT, Fraser ID, Hu LA, Chen W, Pitcher JA, Scott JD, Lefkowitz RJ. Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79. J Biol Chem. 2001;276:15192–9.  https://doi.org/10.1074/jbc.M009130200.CrossRefPubMedGoogle Scholar
  12. Eijkelkamp N, Heijnen CJ, Willemen HLDM, Deumens R, Joosten EAJ, Kleibeuker W, den Hartog IJM, van Velthoven CTJ, Nijboer C, Nassar MA, Dorn 2nd GW, Wood JN, Kavelaars A. GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. J Neurosci. 2010a;30:2138–49.  https://doi.org/10.1523/JNEUROSCI.5752-09.2010.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Eijkelkamp N, Wang H, Garza-Carbajal A, Willemen HLDM, Zwartkruis FJ, Wood JN, Dantzer R, Kelley KW, Heijnen CJ, Kavelaars A. Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK. J Neurosci. 2010b;30:12806–15.  https://doi.org/10.1523/JNEUROSCI.3142-10.2010.CrossRefPubMedGoogle Scholar
  14. Elorza A, Penela P, Sarnago S, Mayor F. MAPK-dependent degradation of G protein-coupled receptor kinase 2. J Biol Chem. 2003;278:29164–73.  https://doi.org/10.1074/jbc.M304314200.CrossRefPubMedGoogle Scholar
  15. Fan J, Malik AB. Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nat Med. 2003;9:315–21.  https://doi.org/10.1038/nm832.CrossRefPubMedGoogle Scholar
  16. Ferrari LF, Bogen O, Alessandri-Haber N, Levine E, Gear RW, Levine JD. Transient decrease in nociceptor GRK2 expression produces long-term enhancement in inflammatory pain. Neuroscience. 2012;222:392–403.  https://doi.org/10.1016/j.neuroscience.2012.07.004.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci. 2004;27:107–44.  https://doi.org/10.1146/annurev.neuro.27.070203.144206.CrossRefPubMedGoogle Scholar
  18. Garcia-Guerra L, Nieto-Vazquez I, Vila-Bedmar R, Jurado-Pueyo M, Zalba G, Díez J, Murga C, Fernández-Veledo S, Mayor F, Lorenzo M. G protein-coupled receptor kinase 2 plays a relevant role in insulin resistance and obesity. Diabetes. 2010;59:2407–17.  https://doi.org/10.2337/db10-0771.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Grange-Midroit M, García-Sevilla JA, Ferrer-Alcón M, La Harpe R, Huguelet P, Guimón J. Regulation of GRK 2 and 6, beta-arrestin-2 and associated proteins in the prefrontal cortex of drug-free and antidepressant drug-treated subjects with major depression. Brain Res Mol Brain Res. 2003;111:31–41.  https://doi.org/10.1016/S0169-328X(02)00667-8.CrossRefPubMedGoogle Scholar
  20. 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.  https://doi.org/10.1161/01.HYP.35.1.38.CrossRefPubMedGoogle Scholar
  21. Gurevich EV, Tesmer JJG, Mushegian A, Gurevich VV. G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther. 2012;133:40–69.  https://doi.org/10.1016/j.pharmthera.2011.08.001.CrossRefPubMedGoogle Scholar
  22. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross J, 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;93:12974–9.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Jiménez-Sainz MC, Murga C, Kavelaars A, Jurado-Pueyo M, Krakstad BF, Heijnen CJ, Mayor F, Aragay AM. G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits. Mol Biol Cell. 2006;17:25–31.  https://doi.org/10.1091/mbc.E05-05-0399.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kim J, Ahn S, Ren X-R, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ. Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling. Proc Natl Acad Sci USA. 2005;102:1442–7.  https://doi.org/10.1073/pnas.0409532102.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Li AH, Wang H-L. G protein-coupled receptor kinase 2 mediates μ-opioid receptor desensitization in GABAergic neurons of the nucleus raphe magnus. J Neurochem. 2001;77:435–44.  https://doi.org/10.1046/j.1471-4159.2001.00267.x.CrossRefPubMedGoogle Scholar
  26. Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJG. Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gbetagamma. Science. 2003;300:1256–62.  https://doi.org/10.1126/science.1082348.CrossRefPubMedGoogle Scholar
  27. Lombardi MS, Kavelaars A, Schedlowski M, Bijlsma JW, Okihara KL, Van de Pol M, Ochsmann S, Pawlak C, Schmidt RE, Heijnen CJ. Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis. FASEB J. 1999;13:715–25.PubMedCrossRefGoogle Scholar
  28. Lombardi MS, Kavelaars A, Cobelens PM, Schmidt RE, Schedlowski M, Heijnen CJ. Adjuvant arthritis induces down-regulation of G protein-coupled receptor kinases in the immune system. J Immunol. 2001;166:1635–40.  https://doi.org/10.4049/jimmunol.166.3.1635.CrossRefPubMedGoogle Scholar
  29. Lombardi MS, Kavelaars A, Penela P, Scholtens EJ, Roccio M, Schmidt RE, Schedlowski M, Mayor F, Heijnen CJ. Oxidative stress decreases G protein-coupled receptor kinase 2 in lymphocytes via a calpain-dependent mechanism. Mol Pharmacol. 2002;62:379–88.  https://doi.org/10.1124/mol.62.2.379.CrossRefPubMedGoogle Scholar
  30. Lombardi MS, van den Tweel E, Kavelaars A, Groenendaal F, van Bel F, Heijnen CJ. Hypoxia/ischemia modulates G protein-coupled receptor kinase 2 and beta-arrestin-1 levels in the neonatal rat brain. Stroke. 2004;35:981–6.  https://doi.org/10.1161/01.STR.0000121644.82596.7e.CrossRefPubMedGoogle Scholar
  31. Lorenz K, Lohse MJ, Quitterer U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature. 2003;426:574–9.  https://doi.org/10.1038/nature02158.CrossRefPubMedGoogle Scholar
  32. Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med. 2007;13:315-23. doi:10.1038/nm1553.CrossRefPubMedGoogle Scholar
  33. Mariggiò S, García-Hoz C, Sarnago S, De Blasi A, Mayor Jr F, Ribas C. Tyrosine phosphorylation of G-protein-coupled-receptor kinase 2 (GRK2) by c-Src modulates its interaction with Gαq. Cell Signal. 2006;18:2004–12.  https://doi.org/10.1016/j.cellsig.2006.03.004.CrossRefPubMedGoogle Scholar
  34. Matkovich SJ, Diwan A, Klanke JL, Hammer DJ, Marreez Y, Odley AM, Brunskill EW, Koch WJ, Schwartz RJ, Dorn 2nd GW. Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling. Circ Res. 2006;99:996–1003.  https://doi.org/10.1161/01.RES.0000247932.71270.2c.CrossRefPubMedGoogle Scholar
  35. Mehta N, Cheng AH, Chiang C-K, Mendoza-Viveros L, Ling HH, Patel A, Xu B, Figeys D, Cheng H-YM. GRK2 Fine-tunes circadian clock speed and entrainment via transcriptional and post-translational control of PERIOD proteins. Cell Rep. 2015;12:1272–88.  https://doi.org/10.1016/j.celrep.2015.07.037.CrossRefPubMedGoogle Scholar
  36. Morisco C, Lembo G, Trimarco B. Insulin resistance and cardiovascular risk: new insights from molecular and cellular biology. Trends Cardiovasc Med. 2006;16:183–8.  https://doi.org/10.1016/j.tcm.2006.03.008.CrossRefPubMedGoogle Scholar
  37. Naga Prasad SV, Laporte SA, Chamberlain D, Caron MG, Barak L, Rockman HA. Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J Cell Biol. 2002;158:563–75.  https://doi.org/10.1083/jcb.200202113.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Nijboer CH, Heijnen CJ, Willemen HLDM, Groenendaal F, Dorn 2nd GW, van Bel F, Kavelaars A. Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice. Brain Behav Immun. 2010;24:420–6.  https://doi.org/10.1016/j.bbi.2009.11.009.CrossRefPubMedGoogle Scholar
  39. Nogués L, Salcedo A, Mayor Jr F, Penela P. Multiple scaffolding functions of β-arrestins in the degradation of G protein-coupled receptor kinase. J Biol Chem. 2011;286:1165–73.  https://doi.org/10.1074/jbc.M110.203406.CrossRefPubMedGoogle Scholar
  40. Ozaita A, Escribá PV, Ventayol P, Murga C, Mayor Jr F, García-Sevilla JA. Regulation of G protein-coupled receptor kinase 2 in brains of opiate-treated rats and human opiate addicts. J Neurochem. 1998;70:1249–57.  https://doi.org/10.1046/j.1471-4159.1998.70031249.x.CrossRefPubMedGoogle Scholar
  41. Palczewski K. GTP-binding-protein-coupled receptor kinases. Eur J Biochem. 1997;248:261–9.  https://doi.org/10.1111/j.1432-1033.1997.00261.x.CrossRefPubMedGoogle Scholar
  42. Patial S, Luo J, Porter KJ, Benovic JL, Parameswaran N. G-protein coupled receptor kinases mediate TNFa induced NFkB signaling via direct interaction with and phosphorylation of IkBa. Biochemistry. 2009;425:169–78.  https://doi.org/10.1042/BJ20090908.G-PROTEIN.CrossRefGoogle Scholar
  43. Penela P, Elorza A, Sarnago S, Mayor Jr F. Beta-arrestin- and c-Src-dependent degradation of G-protein-coupled receptor kinase 2. EMBO J. 2001;20:5129–38.  https://doi.org/10.1093/emboj/20.18.5129.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Penela P, Rivas V, Salcedo A, Mayor Jr F. G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc Natl Acad Sci USA. 2010;107:1118–23.  https://doi.org/10.1073/pnas.0905778107.CrossRefPubMedGoogle Scholar
  45. Pitcher JA, Tesmer JJ, Freeman JL, Capel WD, Stone WC, Lefkowitz RJ. Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases. J Biol Chem. 1999;274:34531–4.  https://doi.org/10.1074/jbc.274.49.34531.CrossRefPubMedGoogle Scholar
  46. Pronin AN, Morris AJ, Surguchov A, Benovic JL. Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem. 2000;275:26515–22.  https://doi.org/10.1074/jbc.M003542200.CrossRefPubMedGoogle Scholar
  47. Ramos-Ruiz R, Penela P, Penn RB, Mayor Jr F. Analysis of the human G protein-coupled receptor kinase 2 (GRK2) gene promoter: regulation by signal transduction systems in aortic smooth muscle cells. Circulation. 2000;101:2083–9.  https://doi.org/10.1161/01.CIR.0000108925.95658.8D.CrossRefPubMedGoogle Scholar
  48. Ren X-R, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc Natl Acad Sci USA. 2005;102:1448–53.  https://doi.org/10.1073/pnas.0409534102.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rengo G, Leosco D, Zincarelli C, Marchese M, Corbi G, Liccardo D, Filippelli A, Ferrara N, Lisanti MP, Koch WJ, 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:H2032–8.  https://doi.org/10.1152/ajpheart.00702.2009.CrossRefPubMedGoogle Scholar
  50. Salcedo A, Mayor Jr F, Penela P. Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2. EMBO J. 2006;25:4752–62.  https://doi.org/10.1038/sj.emboj.7601351.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Sarnago S, Elorza A, Mayor Jr F. Agonist-dependent phosphorylation of the G protein-coupled receptor kinase 2 (GRK2) by Src tyrosine kinase. J Biol Chem. 1999;274:34411–6.  https://doi.org/10.1074/jbc.274.48.34411.CrossRefPubMedGoogle Scholar
  52. Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ G, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015;7:277ra31.  https://doi.org/10.1126/scitranslmed.aaa0154.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Shiina T, Arai K, Tanabe S, Yoshida N, Haga T, Nagao T, Kurose H. Clathrin box in G protein-coupled receptor kinase 2. J Biol Chem. 2001;276:33019–26.  https://doi.org/10.1074/jbc.M100140200.CrossRefPubMedGoogle Scholar
  54. Suo Z, Wu M, Citron BA, Wong GT, Festoff BW. Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer’s disease: an association with early b-amyloid accumulation. J Neurosci. 2004;24:3444–52.  https://doi.org/10.1523/JNEUROSCI.4856-03.2004.CrossRefPubMedGoogle Scholar
  55. Ungerer M, Parruti G, Bohm M, Puzicha M, DeBlasi A, Erdmann E, Lohse MJ. Expression of beta-arrestins and beta-adrenergic receptor kinases in the failing human heart. Circ Res. 1994;74:206–13.  https://doi.org/10.1161/01.RES.74.2.206.CrossRefPubMedGoogle Scholar
  56. Usui I, Imamura T, Satoh H, Huang J, Babendure JL, Hupfeld CJ, Olefsky JM. GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. EMBO J. 2004;23:2821–9.  https://doi.org/10.1038/sj.emboj.7600297.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Usui I, Imamura T, Babendure JL, Satoh H, Lu J-C, Hupfeld CJ, Olefsky JM. G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes. Mol Endocrinol. 2005;19:2760–8.  https://doi.org/10.1210/me.2004-0429.CrossRefPubMedGoogle Scholar
  58. Vroon A, Lombardi MS, Kavelaars A, Heijnen CJ. Changes in the G-protein-coupled receptor desensitization machinery during relapsing-progressive experimental allergic encephalomyelitis. J Neuroimmunol. 2003;137:79–86.  https://doi.org/10.1016/S0165-5728(03)00050-X.CrossRefPubMedGoogle Scholar
  59. Vroon A, Heijnen CJ, Lombardi MS, Cobelens PM, Mayor Jr F, Caron MG, Kavelaars A. Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4. J Leukoc Biol. 2004;75:901–9.  https://doi.org/10.1189/jlb.0403136.CrossRefPubMedGoogle Scholar
  60. Vroon A, Kavelaars A, Limmroth V, Lombardi MS, Goebel MU, Van Dam A-M, Caron MG, Schedlowski M, Heijnen CJ. G protein-coupled receptor kinase 2 in multiple sclerosis and experimental autoimmune encephalomyelitis. J Immunol. 2005;174:4400–6.  https://doi.org/10.4049/jimmunol.174.7.4400.CrossRefPubMedGoogle Scholar
  61. Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell. 2007;129:511–22.  https://doi.org/10.1016/j.cell.2007.02.046.CrossRefPubMedGoogle Scholar
  62. Willemen HLDM, Eijkelkamp N, Wang H, Dantzer R, Dorn 2nd GW, Kelley KW, Heijnen CJ, Kavelaars A. Microglial/macrophage GRK2 determines duration of peripheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain. 2010;150:550–60.  https://doi.org/10.1016/j.pain.2010.06.015.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ. Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev. 2013;65:223–54.  https://doi.org/10.1124/pr.112.005942.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Winstel R, Freund S, Krasel C, Hoppe E, Lohse MJ. Protein kinase cross-talk: membrane targeting of the beta-adrenergic receptor kinase by protein kinase C. Proc Natl Acad Sci USA. 1996;93:2105–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Wu J-H, Goswami R, Kim LK, Miller WE, Peppel K, Freedman NJ. The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition. J Biol Chem. 2005;280:31027–35.  https://doi.org/10.1074/jbc.M501473200.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiologyUniversity of Toronto MississaugaMississaugaCanada
  2. 2.Department of Cell and Systems BiologyUniversity of TorontoTorontoCanada