Mechanisms involved in adrenergic receptor desensitization.

The various subtypes of receptors for catecholamines, termed adrenergic receptors, represent excellent models for the study of receptor-mediated transmembrane signalling because of their ubiquity, their coupling to well-defined effector mechanisms, and the clinical importance of drugs which interact with them. In general, the adrenergic receptor systems consist of three components which are coupled to each other: ( i ) the receptor, to which the hormone binds; ( i i ) a guanine nucleotide regulatory protein (or G-protein) and (iii) an effector enzyme. Each of the major adrenergic receptor subtypes, B, , Bz, a , and a2, are classically defined pharmacologically, and are coupled to well-defined plasma membrane effector systems which generate second messengers. Activation of the Badrenergic receptors leads to the stimulation of adenylate cyclase and the generation of cyclic AMP, which in turn can activate the cyclic AMP-dependent protein kinase (PKA). Subsequent phosphorylation of key substrates in a cell can then give rise to specific cellular responses. Likewise, the a*adrenergic receptor inhibits adenylate cyclase through coupling to G,, thus also regulating levels of the second messenger cyclic AMP. Activation of the a ,-adrenergic receptor stimulates hydrolysis of phosphoinositol bisphosphate (PIP,), to the two second-messengers, inositol trisphosphate (IPJ. and diacylglycerol, and the activation of protein kinase C. This review will focus on recent progress in elucidating the structure, function and regulation of adrenergic receptors, particularly the B,-adrenergic receptor (B,AR), and emphasize the regulation of signal transduction by the second messenger cyclic AMP.