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Osmotic swelling-provoked release of organic osmolytes in human intestinal epithelial cells. Am J Physiol Cell Physiol 286: C1417-C1422, 2004. First published February 11, 2004; 10.1152/ajpcell.00468.2003.--Human Intestine 407 cells respond to osmotic cell swelling by the activation of [Cl.sup.-] and [K.sup.+] -selective ionic channels, as well as by stimulating an organic osmolyte release pathway readily permeable to taurine and phosphocholine. Unlike the activation of volume-regulated anion channels (VRAC), activation of the organic osmolyte release pathway shows a lag time of ~30-60 s, and its activity persists for at least 8-12 min. In contrast to VRAC activation, stimulation of organic osmolyte release did not require protein tyrosine phosphorylation, active p[21.sup.rho], or phosphatidylinositol 3-kinase activity and was insensitive to [Cl.sup.-] channel blockers. Treatment of the cells with putative organic anion transporter inhibitors reduced the release of taurine only partially or was found to be ineffective. The efflux was blocked by a subclass of organic cation transporter (OCT) inhibitors (cyanine-863 and decynium-22) but not by other OCT inhibitors (cimetidine, quinine, and verapamil). Brief treatment of the cells with phorbol esters potentiated the cell swelling-induced taurine efflux, whereas addition of the protein kinase C (PKC) inhibitor GF109203X largely inhibited the response, suggesting that PKC is involved. Increasing the level of intracellular [Ca.sup.2+] by using A-23187-or [Ca.sup.2+]-mobilizing hormones, however, did not affect the magnitude of the response. Taken together, the results indicate that the hypotonicity-induced efflux of organic osmolytes is independent of VRAC and involves a PKC-dependent step. regulatory volume decrease; taurine; volume-regulated anion channels; chloride channel; protein kinase C