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 to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a signaling switch for G protein-coupled receptors.[7]
GRK4 is most highly expressed in the testes, with low amounts in brain and kidney and other tissues, and has four alternatively-spliced variants.[8]
Polymorphisms in the GRK4 gene have been linked to both genetic and acquired hypertension, acting in part through kidney dopamine receptors.[9][10]
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^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Ambrose C, James M, Barnes G, Lin C, Bates G, Altherr M, Duyao M, Groot N, Church D, Wasmuth JJ, et al. (Jun 1993). "A novel G protein-coupled receptor kinase gene cloned from 4p16.3". Hum Mol Genet. 1 (9): 697–703. doi:10.1093/hmg/1.9.697. PMID1338872.
^Premont RT, Inglese J, Lefkowitz RJ (1995). "Protein kinases that phosphorylate activated G protein-coupled receptors". FASEB J. 9 (2): 175–182. doi:10.1096/fasebj.9.2.7781920. PMID7781920. S2CID20428064.
Sallese M, Lombardi MS, De Blasi A (1994). "Two isoforms of G protein-coupled receptor kinase 4 identified by molecular cloning". Biochem. Biophys. Res. Commun. 199 (2): 848–54. doi:10.1006/bbrc.1994.1306. PMID8135832.
Speirs HJ, Katyk K, Kumar NN, et al. (2004). "Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension". J. Hypertens. 22 (5): 931–6. doi:10.1097/00004872-200405000-00014. PMID15097232. S2CID40225611.
Rankin ML, Marinec PS, Cabrera DM, et al. (2006). "The D1 dopamine receptor is constitutively phosphorylated by G protein-coupled receptor kinase 4". Mol. Pharmacol. 69 (3): 759–69. doi:10.1124/mol.105.019901. PMID16338988. S2CID509393.
Wang Y, Li B, Zhao W, et al. (2006). "Association study of G protein-coupled receptor kinase 4 gene variants with essential hypertension in northern Han Chinese". Ann. Hum. Genet. 70 (Pt 6): 778–83. doi:10.1111/j.1469-1809.2006.00278.x. PMID17044852. S2CID46694387.
Wang Z, Armando I, Asico LD, et al. (2007). "The elevated blood pressure of human GRK4gamma A142V transgenic mice is not associated with increased ROS production". Am. J. Physiol. Heart Circ. Physiol. 292 (5): H2083–92. doi:10.1152/ajpheart.00944.2006. PMID17259440.