Mechanisms of receptor activation in adenylate cyclase systems

Recent years have seen a dramatic increase in our knowledge of the structure, function, and regulation of hormone-sensitive adenylate cyclase systems. The detailed structure of receptors and guanine nucleotide binding proteins (G proteins) are now known. Biochemical techniques for the in vitro reconstitution of purified components have facilitated the study of how these components interact to promote the transmembrane signalling process. It is now clear that agonists but not antagonists induce a whole series of interactions beginning with protein conformational changes in the receptor followed by activation of a specific guanine nucleotide binding protein consequent to GTP binding. The activated G protein ultimately results in activation of the enzyme adenylate cyclase with the catalysis of ATP to cAMP. A multitude of studies have demonstrated that each of these components and their interactions can be modulated by a variety of pathophysiological states. Partial agonists represent a class of drugs that can fully occupy receptors, yet induce a less than maximal response compared to full agonists. The mechanism by which these agents produce a less than full response remains unclear, but several possibilities exist. These putative mechanisms, as well as the role of partial agonists in regulating adenylate cyclase systems, will be discussed in detail.