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in Chloride Secretory Epithelia
1 Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
2 Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; University of Vienna Medical School, Vienna, Austria
* To whom correspondence should be addressed. E-mail: Jeffrey.Matthews{at}uc.edu.
In secretory epithelia, activation of protein kinase C (PKC) by phorbol ester and carbachol negatively regulates Cl- secretion, the transport event of secretory diarrhea. Previous studies have implicated the basolateral Na-K-2Cl cotransporter NKCC1 as a target of PKC-dependent inhibition of chloride secretion. In the present study, we examined the regulation of surface expression of NKCC1 in response to activation of PKC. Treatment of confluent T84 intestinal epithelial cells with the phorbol ester PMA reduced the amount of NKCC1 accessible to basolateral surface biotinylation. Loss of cell surface NKCC1 was due to internalization, as shown by resistance of biotinylated NKCC1 to surface biotin stripping after incubation with PMA and by indirect immunofluorescent labeling. PMA-induced internalization of NKCC1 is dependent on the 
isoform of PKC as determined by sensitivity to a panel of PKC inhibitors. The effect of PMA on surface expression of NKCC1 was specific, since PMA did not significantly alter the amount of Na-K ATPase or E-cadherin available for surface biotinylation. After extended PMA exposure (> 2 hrs), NKCC1 became degraded in a proteasome-dependent fashion. Like PMA, carbachol reduced the amount of NKCC1 accessible to basolateral surface biotinylation in a PKC-dependent manner. However, long-term exposure to carbachol did not result in degradation of NKCC1; rather, NKCC1 internalized after exposure to carbachol recycled back to the cell membrane. PKC-dependent alteration of NKCC1 surface expression represents a novel mechanism for regulating Cl- secretion.
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