G protein-coupled receptor kinase 2, also known as beta-adrenergic receptor kinase 1, is a member of the GRK family, which phosphorylates the activated form of G protein-coupled receptors and initiates the desensitization process of GPCR. GRK2 kinase activity and cellular localization are tightly regulated by interactions with activated receptors, G-beta and G-gamma subunits, adaptor proteins, phospholipids, caveolin, and calmodulin, as well as by phosphorylation. Protein kinase C phosphorylation enhances GRK2 activity by promoting its membrane localization and by abolishing the inhibitory association of calmodulin. Protein kinase A phosphorylates GRK2 at Ser685, facilitating the association of GRK2 with a beta-adrenergic receptor. Erk inhibits GRK2 activity via phosphorylation at Ser670. Src phosphorylates GRK2 at multiple tyrosine residues, which activates GRK2 activity and promotes GRK2 degradation.
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