Molecular Regulation of Na+‐K+‐2C1‐ Cotransporter (NKCC1) and Epithelial Chloride Secretion

Defective regulation of epithelial secretion underlies the clinical manifestations of a number of important human diseases ranging from cystic fibrosis to secretory diarrhea. Although much attention has focused on the role of apical membrane chloride (Cl-) channels in this process, emerging evidence highlights the importance of a basolateral Na+-K+-2Cl- cotransporter (NKCC1) as an independent regulatory site that may determine the overall rate of epithelial secretion. The cotransporter NKCC1 is expressed not only in epithelial cells but also in virtually all mammalian cells, where it plays a more generalized role in cell volume homeostasis, cell ionic composition, and, possibly, the control of cell growth. Emerging molecular evidence indicates that NKCC1 function is regulated in the short and long term at the level of protein phosphorylation, membrane targeting, and gene expression. An improved understanding of NKCC1 may lead to new therapeutic approaches to secretory diarrhea as well as diverse clinical conditions in which cell ion composition is disturbed.