G Protein-coupled Receptors

Of the many forms of GPCR regulation none has received as much attention as the process of receptor desensitization, i.e. the waning responsiveness of the receptors in the face of persistent stimulation (1, 2). Numerous mechanisms have been discovered, including those that operate at the transcriptional, translational, and protein levels. The latter category in turn includes mechanisms that regulate the rate of degradation of the receptors. Finally, there are mechanisms for the covalent modification of the receptors as well as for the regulation of their association with other proteins and their subcellular localization (1–3). This brief review is concerned with this last group of mechanisms, which appears to be most important with respect to the rapid (seconds– minutes as opposed to hours or days) control of receptor function. Traditionally, receptor desensitization has been viewed as a process antithetical to receptor activation, one which terminates or attenuates receptor signaling. Three families of regulatory molecules have been found to participate in desensitization of heptahelical receptors: second messenger-regulated kinases (e.g. PKA and PKC), GRKs (e.g. bARK, rhodopsin kinase), and the arrestins (visual and non-visual). After briefly reviewing the well established paradigms for regulation of GPCRs by these three families of molecules, I will attempt to demonstrate how newly acquired insights into the function of these receptor regulatory molecules are reshaping understanding of the classical dichotomy between receptor activation and desensitization. The new information suggests that receptor signaling and desensitization are in reality two intimately linked aspects of receptor function and that mechanisms previously viewed as “desensitizing” with respect to one signaling pathway may be “activating” with respect to another.