Epithelial ion secretion: (a) Na⁺, K⁺, and 2 Cl^– ions are transported into the cell by the NaK2Cl cotransporter (NKCC). Na⁺ and K⁺ are recycled across the basolateral surface by the NaK-ATPase and a K⁺ channel, respectively. The activity of intracellular Cl^– is above electrochemical equilibrium. The apical membrane contains the CFTR, a cyclic AMP-activated Cl^– channel. When opened, CFTR-mediated Cl^– secretion results in hyperpolarization of the epithelium leading to secretion of Na⁺ in between the cells. (b) The CFTR is inhibited by thiazolidinone derivatives. (c) In cystic fibrosis epithelia, the CFTR is either not delivered to the apical surface or cannot be opened by cyclic AMP. (d) In secretory diarrhea, an increase in cyclic AMP or cyclic GMP opens the CFTR and leads to increased Cl^– secretion.