Guanylyl cyclases and signaling by cyclic GMP

Guanylyl cyclases are a family of enzymes that catalyze the conversion of G TP to cGMP. The family comprises both membrane-bound and soluble isoforms t hat are expressed in nearly all cell types. They are regulated by diverse e xtracellular agonists that include peptide hormones, bacterial toxins, and free radicals, as well as intracellular molecules, such as calcium and aden ine nucleotides. Stimulation of guanylyl cyclases and the resultant accumul ation of cGMP regulates complex signaling cascades through immediate downst ream effectors, including cGMP-dependent protein kinases, cGMP-regulated ph osphodiesterases, and cyclic nucleotide-gated ion channels. Guanylyl cyclas es and cGMP-mediated signaling cascades play a central role in the regulati on of diverse (patho)physiological processes, including vascular smooth mus cle motility, intestinal fluid and electrolyte homeostasis, and retinal pho totransduction. Topics addressed in this review include the structure and c hromosomal localization of the genes for guanylyl cyclases, structure and f unction of the members of the guanylyl cyclase family, molecular mechanisms regulating enzymatic activity, and molecular sequences coupling ligand bin ding to catalytic activity. A brief overview is presented of the downstream events controlled by guanylyl cyclases, including the effectors that are r egulated by cGMP and the role that guanylyl cyclases play in cell physiolog y and pathophysiology.