With at least 1000 family members encoded by mammalian genomes, the G protein-coupled receptors (GPCRs) represent the most diverse group of signaling proteins known (Bockaert and Pin, 1999). GPCRs are involved in the regulation of a wide variety of physiological processes including, but not limited to, the sensory perceptions of pain, light, odors and tastes, cognition, muscle contraction, endocrine and exocrine secretion, metabolism, inflammation, and immunity. The classic paradigm of the GPCR signal transduction process is that upon ligand binding, conformational changes in the receptor arise that allow it to couple to the heterotrimeric G proteins. This coupling stimulates the G protein to alter the activity of a variety of downstream effector molecules (Neer, 1995). In addition to G protein coupling, activation of a GPCR by its ligand also initiates the process of receptor desensitization, an adaptive response used by cells to arrest G protein signaling, therefore preventing the potentially harmful effects that can result from persistent receptor stimulation.

Almost every GPCR that has been studied undergoes desensitization and, despite their diversity, all cells use a universal mechanism for desensitizing GPCRs. This involves the coordinated actions of two families of proteins, the G proteincoupled receptor serine/threonine kinases (GRKs) and the arrestins (Freedman and Lefkowitz, 1996; Krupnick and Benovic, 1998; Pitcher et al., 1998; Ferguson, 2001). After binding to its agonist, a GPCR assumes a conformation that allows it to bind one or more of the GRKs (of which there are seven) and, in doing so, becomes phosphorylated at residues on its intracellular loops and carboxyl terminus. Phosphorylation of the receptor promotes the high-affinity binding of the arrestin family of proteins (of which there are four) to the