Genetic Investigation of Adenylate Cyclase: Mutations in Mouse and Man

As a pivotal control point in cardiovascular, neural, endocrine, and meta­ bolic regulation, hormone-sensitive adenylate cyclase serves as the target for drugs used in treating disorders of almost every organ system. How do drugs and hormones stimulate adenylate cyclase? The methods of molecu­ lar pharmacology and biochemistry have provided most of the experimental facts: Radioligand binding studies have allowed characterization of the molecular properties of membrane receptors and established that recep­ tors are physically separable from the catalytic unit that synthesizes cyclic adenosine 3',5'-monophosphate (cAMP) from ATP (1-5). Purifica­ tion of plasma membranes has allowed precise kinetic studies of regu­ lation of cAMP synthesis, and has led to the discovery that guanine nucleotides regulate both cAMP synthesis and binding of agonists to recep­ tors (6-10). For detailed accounts of the biochemical characterization of adenylate cyclase and possible interactions of its components in membranes, we refer the reader to several recent reviews (11-13). Here we review results of an experimental approach, based on the concepts and techniques of somatic genetics, that has contributed significantly to our current understanding of adenylate cyclase. This approach has helped to define a membrane protein,