Regulation of G-protein-coupled receptor kinase subtypes by calcium sensor proteins

The process of G-protein-coupled receptor (GPCR) homologous desensitization is intrinsically related to the function of a class of S/T kinases named G-protein-coupled receptor kinases (GRK). GRK family is so far composed of six cloned members, named GRK1 to 6, which are classified into three subfamilies: GRK1 is alone in the first (rhodopsin kinase subfamily), GRK2 and 3 form the second [beta-adrenergic receptor kinase (betaARK) subfamily], and GRK4, 5, and 6 constitute the third (GRK4 subfamily). Recent studies from different laboratories have demonstrated that different calcium sensor proteins (CSP) can selectively regulate the activity of GRK subtypes. In the presence of calcium, rhodopsin kinase (GRK1) is inhibited by the photoreceptor-specific CSP recoverin through direct binding. Several other recoverin homologues (including NCS 1, VILIP 1, and hippocalcin) are also able to inhibit GRK1 in a calcium-dependent manner. The ubiquitous calcium binding protein calmodulin (CaM) can inhibit GRK5 with a high affinity (IC50=40-50 nM). A direct interaction between GRK5 and Ca2+/CaM was documented and this binding did not influence the catalytic activity of the kinase, but rather reduced GRK5 binding to the membrane. These studies suggest that CSP act as functional analogs in mediating the regulation of different GRK subtypes by Ca2+. This mechanism, however, is highly selective with respect to the GRK subtypes: GRK1, but not GRK2 and GRK5, is regulated by recoverin and other NCS, but GRK4, 5, and 6, which belong to the GRK4 subfamily are potently inhibited by CaM, which has little or no effect on members of other GRK subfamilies. Calcium-dependent inhibition of rhodopsin kinase by recoverin represents one of the mechanisms that control adaptation to light. For the other GPCR, CSP-GRK interaction provides a feedback mechanism that can modulate homologous desensitization of these receptors.