Guanylyl cyclase structure, function and regulation

Abstract

Nitric oxide, bicarbonate, natriuretic peptides (ANP, BNP and CNP), guanylins, uroguanylins and guanylyl cyclase activating proteins (GCAPs) activate a family of enzymes variously called guanyl, guanylyl or guanylate cyclases that catalyze the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP) and pyrophosphate. Intracellular cyclic GMP is a second messenger that modulates: platelet aggregation, neurotransmission, sexual arousal, gut peristalsis, blood pressure, long bone growth, intestinal fluid secretion, lipolysis, phototransduction, cardiac hypertrophy and oocyte maturation. This review briefly discusses the discovery of cGMP and guanylyl cyclases, then nitric oxide, nitric oxide synthase and soluble guanylyl cyclase are described in slightly greater detail. Finally, the structure, function, and regulation of the individual mammalian single membrane-spanning guanylyl cyclases GC-A, GC-B, GC-C, GC-D, GC-E, GC-F and GC-G are described in greatest detail as determined by biochemical, cell biological and gene-deletion studies.

Fig. 1

Schematic of mammalian guanylyl cyclases and their ligands. Seven transmembrane and four soluble guanylyl cyclases are expressed in mammals. The structure and function of each member is discussed in the text. Similarity of extracellular domain color represents primary amino acid sequence similarity between receptors. The blue “P” indicates known phosphorylation sites. The black bar between NPR-C subunits indicates intermolecular disulfide bond. Abbreviations are: ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; CO, carbon monoxide; CO₂/HCO₃, carbon dioxide/bicarbonate; GCAPs, guanylyl cyclase activator proteins; Gn, guanylin; Hb, hemoglobin; NO, nitric oxide; NPR-C, natriuretic peptide receptor C; Sta, heat-stable enterotoxin; Uro, uroguanylin.