Regulation of Particulate Guonylate Cyclase by Notriuretic Peptides and Escherichia coli Heat-Stable Enterotoxin

Abstract

This chapter illustrates that the signal transducing enzyme guanylate cyclase is activated in response to specific extracellular signals, leading to the formation of the intracellular second messenger—cyclic guanosine monophosphate (GMP). Two isoenzyme forms of guanylate cyclase exist in cells, which are physically and biochemically distinct and regulated by different agents. The soluble isoenzyme of guanylate cyclase, located in the cytosol, is a heterodimer composed of 70- and 82-kDa subunits and is activated by nitrate containing compounds, endothelial-derived relaxing factors, and oxytocin. A second isoenzyme called “particulate guanylate cyclase” is located in the cell membrane. Enterotoxigenic Escherichia coli elaborate heat-stable enterotoxin (ST), a plasmid-encoded low-molecular-weight peptide exotoxin that produces profuse watery diarrhea by increasing fluid and electrolyte secretion in the intestinal mucosa. A mammalian homologue of this peptide termed “guanylin” has been identified in small intestinal cells and presumably mediates local fluid and electrolyte balance in that organ. Atrial natriuretic peptide (ANP) has been shown to promote vascular smooth muscle relaxation, inhibit the secretion of renin, vasopressin and aldosterone, and increase the secretion of testosterone and progesterone. It is clear that many of the cellular effects of natriuretic peptides (NP) and ST are mediated by the activation of particulate guanylate cyclase and increase in intracellular concentrations of cyclic GMP. The chapter describes the membrane receptors for ANP and ST and particulate guanylate cyclase to which they are coupled.