Mechanisms for Hormonal Regulation of the Different Isoforms of Guanylate Cyclase

Abstract

Cyclic GMP was first described in urine and other biological samples more than 25 years ago. The description and characterization of the enzymes responsible for cyclic GMP synthesis (guanylate cyclase), cyclic GMP hydrolysis (phosphodiesterase), and expression of some of the effects of cyclic GMP (cyclic GMP-dependent protein kinase) followed shortly thereafter. It soon became apparent that various hormones could increase cyclic GMP synthesis and accumulation in different tissues. Thus, it was anticipated that cyclic GMP would serve as a second messenger of many hormone-induced responses (see Murad 1986; Murad et al. 1978, 1979, 1988; Waldman and Murad 1987). However, the mechanisms of hormone-induced cyclic GMP accumulation in tissues and the coupling of hormone receptors to cyclic GMP synthesis have remained unresolved until the past several years. The major difficulties in answering these interesting questions are due to the multiple isoenzyme forms of guanylate cyclase, the diverse mechanisms of hormone-receptor coupling to the regulation of each of these isoenzymes, and the failure of hormones to activate the enzyme in cell-free preparations. The detailed characterization and purification of these isoforms of guanylate cyclase in our laboratory and others have permitted us to begin to understand the mechanisms of hormonal regulation of the guanylate cyclase isoenzyme family. Some of the properties of the isoforms of guanylate cyclase and the mechanisms of hormone-receptor coupling to each of these isoforms will be briefly reviewed here. Interestingly, the four isoenzyme forms of guanylate cyclase that have been described to date are each uniquely coupled to hormonal regulation.