NEW INSIGHTS INTO THE UP-REGULATION AND FUNCTION OF THE SALIVARY NA-K+-2CL(-) COTRANSPORTER()

In many exocrine epithelia, the Na+-K+-2Cl(-) cotransporter is the mai n provider of cellular chloride entry during transepithelial salt and water secretion. Because of its accessibility and hormonal responsiven ess, the salivary gland has recently emerged as a convenient preparati on in which to study the regulation and characteristics of this transp ort protein. In this review, we summarize recent findings from our lab oratory which demonstrate that muscarinic, alpha(1)-adrenergic and pep tidergic stimulation of rat parotid acinar cells induce a dramatic (up to twenty-fold) upregulation of Na+-K+-2Cl(-) cotransporter activity. Our results indicate that this effect is dependent on the rise in int racellular calcium concentration ([Ca2+](i)) that accompanies stimulat ion, and is not a consequence of the KCl loss and the concomitant cell shrinkage associated with fluid secretion. In addition, we show that the effect of muscarinic stimulation on the cotransporter can be block ed by inhibitors of phospholipase A(2,) by a general inhibitor of arac hidonic acid metabolism, and by specific inhibitors of the cytochrome P450 pathway. These data argue strongly for the involvement of a produ ct of the cytochrome P450 pathway of arachidonic acid metabolism in up regulation of the salivary Na+-K+-2Cl(-) cotransporter.