G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ADRBK2gene.[5] GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK2.[6]
G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. As a result, the G protein-coupled receptors' complicated signaling switch is the GRK/arrestin system.[7]
GRK3 and the closely related GRK2 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast to GRK5 and GRK6, which have the opposite effect).[8][9] This difference is one basis for pharmacological biased agonism (also called functional selectivity), where a drug binding to a receptor may bias that receptor's signaling toward a particular subset of the actions stimulated by that receptor.[10][11]
GRK3 is expressed broadly in tissues, but generally at lower levels than the related GRK2.[12] GRK3 has particularly high expression in olfactory neurons, and mice lacking the ADRBK2 gene exhibit defects in olfaction.[13][14]Gene linkage techniques were used to identify a polymorphism in the promoter of the human ADRBK2 gene as a possible cause of up to 10% of cases of bipolar disorder.[15] However, the significance of GRK3 in bipolar disorder has been controversial due to conflicting reports.[16] GRK3 has also been implicated in regulation of dopamine receptorsinParkinson disease in animal models.[17] Reduced expression of GRK3 has been associated with the immunodeficientWHIM syndrome in humans, and appears causative in a mouse model of the disease.[18][19]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Calabrese G, Sallese M, Stornaiuolo A, Stuppia L, Palka G, De Blasi A (September 1994). "Chromosome mapping of the human arrestin (SAG), beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2) genes". Genomics. 23 (1): 286–8. doi:10.1006/geno.1994.1497. PMID7695743.
^Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, McElroy SL, Alexander M, Shaw SH, Kelsoe JR (May 2003). "Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder". Molecular Psychiatry. 8 (5): 546–57. doi:10.1038/sj.mp.4001268. PMID12808434. S2CID26066432.
^Luykx JJ, Boks MP, Terwindt AP, Bakker S, Kahn RS, Ophoff RA (June 2010). "The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies". European Neuropsychopharmacology. 20 (6): 357–68. doi:10.1016/j.euroneuro.2010.02.008. PMID20226637. S2CID43214075.
Parruti G, Ambrosini G, Sallese M, De Blasi A (January 1993). "Molecular cloning, functional expression and mRNA analysis of human beta-adrenergic receptor kinase 2". Biochemical and Biophysical Research Communications. 190 (2): 475–81. doi:10.1006/bbrc.1993.1072. PMID8427589.
Obara K, Arai K, Tomita Y, Hatano A, Takahashi K (October 2001). "G-protein coupled receptor kinase 2 and 3 expression in human detrusor cultured smooth muscle cells". Urological Research. 29 (5): 325–9. doi:10.1007/s002400100207. PMID11762794. S2CID20860391.
Mandyam CD, Thakker DR, Christensen JL, Standifer KM (August 2002). "Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for heterologous cross-talk". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 502–9. doi:10.1124/jpet.102.033159. PMID12130708. S2CID16475164.
Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, McElroy SL, Alexander M, Shaw SH, Kelsoe JR (May 2003). "Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder". Molecular Psychiatry. 8 (5): 546–57. doi:10.1038/sj.mp.4001268. PMID12808434. S2CID26066432.
Dzimiri N, Muiya P, Andres E, Al-Halees Z (April 2004). "Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases". European Journal of Pharmacology. 489 (3): 167–77. doi:10.1016/j.ejphar.2004.03.015. PMID15087239.
Teli T, Markovic D, Levine MA, Hillhouse EW, Grammatopoulos DK (February 2005). "Regulation of corticotropin-releasing hormone receptor type 1alpha signaling: structural determinants for G protein-coupled receptor kinase-mediated phosphorylation and agonist-mediated desensitization". Molecular Endocrinology. 19 (2): 474–90. doi:10.1210/me.2004-0275. PMID15498832. S2CID22064538.
