G-protein-coupled receptor kinases

beta-Adrenergic receptors are prototypes of the many G-protein-coupled receptors. Activation and inactivation of these receptors are regulated by multiple mechanisms which can affect either their function or their expression. The most obvious changes of such receptor systems are induced by activation of the receptors themselves by their respective agonists, and this process is called receptor desensitization. One of these mechanisms of desensitization is due to the actions of specific receptor kinases, termed the G-protein-coupled receptor kinases (GRKs). These kinases specifically phosphorylate only the agonist-occupied form of such receptors. This phosphorylation is then followed by binding of inhibitor proteins, called arrestins, to the receptors. Binding of arrestins results in displacement of the G-proteins from the receptors and hence causes uncoupling of receptors and G-proteins. Recent data indicate that the function and subcellular distribution of GRKs is itself subject to regulation. Various mechanisms have evolved to anchor the different GRKs to the plasma membrane. In addition, recent data indicate that GRKs can also associate with intracellular membranes where they may exert as yet unknown functions. A pathophysiological role for GRKs can be inferred from recent studies on heart failure as well as the observation that chronic treatment with various agonists or antagonists for G-protein-coupled receptors results in alterations of GRK expression.