G-protein-coupled receptor kinase 2 (GRK2) is anenzyme that in humans is encoded by theADRBK1gene.[5] GRK2 was initially calledBeta-adrenergic receptor kinase (βARK or βARK1), and is a member of theG protein-coupled receptor kinase subfamily of the Ser/Thrprotein kinases that is most highly similar toGRK3(βARK2).[6]
G protein-coupled receptor kinasesphosphorylate activated G protein-coupled receptors, which promotes the binding of anarrestin protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation ofheterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptordesensitization. Arrestin binding also directs receptors to specific cellularinternalization 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. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.[7]
GRK2 and the closely related GRK3 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast toGRK5 andGRK6, which have the opposite effect).[8][9] This difference is one basis for pharmacologicalbiased agonism (also calledfunctional 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]
GRK2 is expressed broadly in tissues, but generally at higher levels than the related GRK3.[12] GRK2 was originally identified as a protein kinase that phosphorylated the β2-adrenergic receptor, and has been most extensively studied as a regulator of adrenergic receptors (and otherGPCRs) in the heart, where it has been proposed as a drug target to treatheart failure.[13][14] Strategies to inhibit GRK2 include using small molecules (includingParoxetine and Compound-101) and using gene therapy approaches utilizing regulatory domains of GRK2 (particularly overexpressing the carboxy terminalpleckstrin-homology (PH) domain that binds theG protein βγ-subunit complex and inhibits GRK2 activation (often called the “βARKct”), or just a peptide from this PH domain).[15][13]
GRK2 and the related GRK3 can interact with heterotrimeric G protein subunits resulting from GPCR activation, both to be activated and to regulate G protein signaling pathways. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein βγ subunits, and GPCR activation of heterotrimeric G proteins releases this free βγ complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor.[16][7] The amino terminalRGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family to reduce Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta; but the GRK2 and GRK3 RH domains are unable to function as GTPase-activating proteins (as do traditionalRGS proteins) to turn off G protein signaling.[17]
^Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB (August 2003). "Differential interaction of GRK2 with members of the G alpha q family".Biochemistry.42 (30):9176–9184.doi:10.1021/bi034442+.PMID12885252.
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