Cellular mechanism of action of heat-stable E. coli enterotoxin (STa). Luminal toxin binds to and activates guanylyl cyclase C (GC), a brush border enzyme with a high rate of expression in both small intestine and proximal colon. The resulting increase in [cGMP] activates membrane-bound protein kinase G (PKG), which, in turn, opens neighboring anion channels or inhibits neighboring Na/H and Cl/HCO3 exchangers (not shown). Guanylin, a mammalian homolog of STa, is the physiologic agonist for the STa-sensitive GC. It is secreted into the lumen by goblet cells. In the duodenum, its action results in an HCO3–-rich secretion.