G protein-coupled receptor kinase

== GRK activity and regulation ==

GRKs reside normally in an inactive state, but their kinase activity is stimulated by binding to a ligand-activated GPCR (rather than by regulatory phosphorylation as is common in other AGC kinases). Because there are only seven GRKs (only 4 of which are widely expressed throughout the body) but over 800 human GPCRs, GRKs appear to have limited phosphorylation site selectivity and are regulated primarily by the GPCR active state. The non-visual GRKs are inhibited instead by the calcium-binding protein calmodulin. == GRK Structures ==

X-ray crystal structures have been obtained for several GRKs (GRK1, GRK2, GRK4, GRK5 and GRK6), alone or bound to ligands. Overall, GRKs share sequence homology and domain organization in which the central protein kinase catalytic domain is preceded by a domain with homology to the active domain of Regulator of G protein Signaling proteins, RGS proteins (the RGS-homology – RH – domain) and is followed by a variable carboxyl terminal tail regulatory region. == GRK physiological functions ==

GRK1 is involved with rhodopsin phosphorylation and deactivation in vision, together with arrestin-1, also known as S-antigen. Defects in GRK1 result in Oguchi stationary night blindness. GRK7 similarly regulates cone opsin phosphorylation and deactivation in color vision, together with cone arrestin, also known as arrestin-4 or X-arrestin. Polymorphisms in the GRK4 gene have been linked to both genetic and acquired hypertension, acting in part through kidney dopamine receptors. In humans, a GRK5 sequence polymorphism at residue 41 (leucine rather than glutamine) that is most common in individuals with African ancestry leads to elevated GRK5-mediated desensitization of airway beta2-adrenergic receptors, a drug target in asthma. In zebrafish and in humans, loss of GRK5 function has been associated with heart defects due to heterotaxy, a series of developmental defects arising from improper left-right laterality during organogenesis. In the mouse, GRK6 regulation of D2 dopamine receptors in the striatum region of the brain alters sensitivity to psychostimulant drugs that act through dopamine, and GRK6 has been implicated in Parkinson's disease and in the dyskinesia side effects of anti-parkinson therapy with the drug L-DOPA. == Non-GPCR functions of GRKs ==

GRKs also phosphorylate non-GPCR substrates. GRK2 and GRK5 can phosphorylate some tyrosine kinase receptors, including the receptor for platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF). GRKs also regulate cellular responses independent of their kinase activity. In particular, G protein-coupled receptor kinase 2 is known to interact with a diverse repertoire of non-GPCR partner proteins, but other GRKs also have non-GPCR partners. The RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family, but despite these RH domains being unable to act as GTPase-activating proteins like traditional RGS proteins to turn off G protein signaling, this binding reduces Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta. == See also ==