Figure 3. Major physiological functions associated with the heat-stable enterotoxin (Sta) from Escherichia coli, guanylin, and uroguanylin in guanylate cyclase C (GC-C) signaling pathways. GC-C is expressed on the surface of the intestinal epithelial cells where it is activated by the STa enterotoxin from E. coli and by the endogenous hormones guanylin and uroguanylin. These endogenous hormones are synthesized in the intestine and secreted into the lumen and blood circulation. GC-C is also a receptor for these peptides that activates the catalytic portion of this protein, resulting in the conversion of guanosine triphosphate to cyclic-guanosine-3′,5′-monophosphate (cGMP). Increased cGMP concentration activates protein kinase GII, which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator, leading to chloride/bicarbonate secretion. In addition, cGMP inhibits the sodium-hydrogen exchanger NHE3, decreasing sodium absorption. Local intestinal secretion of guanylin and uroguanylin co-regulates via GC-C signaling the homeostasis of the crypt-villus axis as well as intestinal barrier function and mechanisms underlying colorectal cancer. High or low salt diets co-regulate local intestinal secretion or systemic circulation of these endogenous hormones, which results in electrolyte and water homeostasis influenced by their effects on the gastrointestinal and urinary tracts. The blood circulation of guanylin and uroguanylin alters the functions of several other systems such as the central nervous system (CNS), cardiovascular system, kidney function, and penile function (see text for further details).