FUNCTION & REGULATION OF GASTRIC NA/K/2CL COTRANSPORTERS

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The gastric mucosa secretes digestive hydrochloric acid and pepsin in coordination with dietary intake. Although it is now axiomatic that parietal cells secrete HCl, a growing body of evidence indicates that these cells undergo major morphological, biochemical, and functional changes as they migrate down into the neck and base of the gastric gland. The nature and functional significance of these changes are poorly understood. We show that parietal cell transformation includes a sudden and prodigious expression of the secretory Na-K-2Cl cotransporter (NKCC). The migration-associated expression of NKCC is topologically correlated with loses of Cl/HCO3 exchanger (AE2) and H,K-ATPase activity, and with expression of aquaporin-4 water channels. We hypothesize that downwardly-migrating parietal cells might undergo a programmed conversion of their principal function from acidic chloride (HCl) secretion to nonacidic chloride (NaCl) secretion. The secretion of a saline fluid volume by parietal cells in the base of the gland might serve to flush the lumen of local pepsinogen and distal acid. The project proposed here consists of four complementary studies. Aim 1 will determine the functional consequences of NKCC expression and AE2 loss during parietal cell migration on intracellular Cl- homeostasis and vectorial Cl- transport by microspectrofluorometric imaging of isolated gastric glands. Aim 2 will begin to delineate the signals, receptors, and intracellular mediators that regulate NKCC in basilar parietal cells in vitro and in vivo. Aim 3 will directly test whether parietal cells in the gland base cease to function as robust acid secretors, as previous evidence has suggested. Finally, Aim 4 will map the cellular and subcellular distribution of K-Cl cotransporter-1 (KCC1) in gastric mucosa and begin to assess the possibility that K-Cl cotransporter-1 (KCC1) may contribute to apical K+ recycling in parietal cells. Completion of these aims will begin to clarify the functional consequences of the migration-associated differentiation of parietal cells.