Mechanisms for Regulation of β-Adrenergic Receptor Function in Desensitization

Abstract

The advent of direct radioligand binding studies of a variety of receptors over the past few years has made it possible to directly investigate the role of receptor alterations in mediating a variety of physiological changes in drug responsiveness. Among the more interesting properties of many biologically active agonist drugs is the fact that they not only stimulate target tissues but they also desensitize them. This means that after a period of agonist stimulation the response of the target tissue often wanes even in the continued presence of the agonist. Many terms have been used to describe these phenomena including desensitization, tolerance, tachyphylaxis and refractoriness. Desensitization is of interest to basic as well as clinical pharmacologists because it may be a major mechanism which limits the therapeutic effectiveness of various drugs. If one could understand the molecular basis for desensitization it might be possible to design therapeutic strategies to alter it. However, since only agonists desensitize tissues (antagonists do not), it seems likely that the activating and desensitizing properties of various agonists are very intimately linked. Thus, a very detailed understanding of these processes is likely to be necesary if they are to be dissected apart.