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Am J Physiol Cell Physiol 281: C649-C661, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 2, C649-C661, August 2001

Regulation of epithelial transport and barrier function by distinct protein kinase C isoforms

Jaekyung Cecilia Song, Celina M. Hanson, Vance Tsai, Omid C. Farokhzad, Margaret Lotz, and Jeffrey B. Matthews

Division of General and Gastrointestinal Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

The phorbol ester phorbol 12-myristate 13-acetate (PMA) inhibits Cl- secretion (short-circuit current, Isc) and decreases barrier function (transepithelial resistance, TER) in T84 epithelia. To elucidate the role of specific protein kinase C (PKC) isoenzymes in this response, we compared PMA with two non-phorbol activators of PKC (bryostatin-1 and carbachol) and utilized three PKC inhibitors (Gö-6850, Gö-6976, and rottlerin) with different isozyme selectivity profiles. PMA sequentially inhibited cAMP-stimulated Isc and decreased TER, as measured by voltage-current clamp. By subcellular fractionation and Western blot, PMA (100 nM) induced sequential membrane translocation of the novel PKCepsilon followed by the conventional PKCalpha and activated both isozymes by in vitro kinase assay. PKCdelta was activated by PMA but did not translocate. By immunofluorescence, PKCepsilon redistributed to the basolateral domain in response to PMA, whereas PKCalpha moved apically. Inhibition of Isc by PMA was prevented by the conventional and novel PKC inhibitor Gö-6850 (5 µM) but not the conventional isoform inhibitor Gö-6976 (5 µM) or the PKCdelta inhibitor rottlerin (10 µM), implicating PKCepsilon in inhibition of Cl- secretion. In contrast, both Gö-6976 and Gö-6850 prevented the decline of TER, suggesting involvement of PKCalpha . Bryostatin-1 (100 nM) translocated PKCepsilon and PKCalpha and inhibited cAMP-elicited Isc. However, unlike PMA, bryostatin-1 downregulated PKCalpha protein, and the decrease in TER was only transient. Carbachol (100 µM) translocated only PKCepsilon and inhibited Isc with no effect on TER. Gö-6850 but not Gö-6976 or rottlerin blocked bryostatin-1 and carbachol inhibition of Isc. We conclude that basolateral translocation of PKCepsilon inhibits Cl- secretion, while apical translocation of PKCalpha decreases TER. These data suggest that epithelial transport and barrier function can be modulated by distinct PKC isoforms.

isoenzymes; intercellular junctions; cytoskeleton; colonic neoplasms; intestinal mucosa; chlorides; intestinal secretion; cystic fibrosis; endocytosis; cell membranes


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