The large family of G protein-coupled receptors (GPCRs) transduces signals of a bewildering variety of extracellular stimuli including hormones, neurotransmitters, ions, cytokines and photons. Many GPCRs undergo a rapid, but reversible decrease or loss of responsiveness upon exposure to their ligand, a phenomenon referred to as homologous desensitization. This process involves an inhibition of the GPCR-interaction with the appropriate G protein and is therefore also coined 'receptor uncoupling'. This rapid form of modulation in responsiveness has to be differentiated from the long-term desensitization caused by transcriptional downregulation (1).
Primarily from studies with rhodopsin and the β-adrenergic receptors, it became apparent that the rapid uncoupling of these GPCRs from the interacting G protein is initiated by phosphorylation of the agonistoccupied, stimulated receptor. Phosphorylation of GPCRs is induced by G protein-coupled receptor kinases (GRKs), a family of serine/threonine kinases with, currently, six known members (2). Once a GPRC is phosphorylated by a