Proposed model for the regulation of ion transport by STa and GC-C and mechanism for cell proliferation in the colon. ETEC elaborate STa in the intestinal lumen. Activation of the GC-C receptor by STa (or guanylin and uroguanylin, which are secreted into the lumen by specific intestinal cells) increases cGMP, which in turn, directly activate cGMP-dependent protein kinase II (PKG-II), cAMP-dependent protein kinase (PKA), and/or cGMP-regulated cAMP phosphodiesterase (PDE) (9). PKG-II activation by cGMP stimulates both Cl
− and HCO

secretion by regulating the CFTR chloride channel, and reduces Na
+ absorption, presumably by inhibiting the Na
+/H
+ exchanger NHE-3. cGMP may activate PKA directly or indirectly (by inhibiting cAMP hydrolysis via PDE, thereby increasing intracellular cAMP levels). PKA, in turn, regulate CFTR activity. Lastly, cGMP can also directly activate the cyclic nucleotide gated (CNG) channels in colon cells, allowing Ca
2+ to enter the cell. Basolateral entry of Cl
−, Na
+, and K
+ occur, in part, through the Na
+-K
+-2Cl
− cotransporter and Na
+/K
+-ATPase. Mechanisms that lead to cellular proliferation or apoptosis presumably are affected downstream of PKG-II/PKA activation and/or Ca
2+ entry.