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J Biol Chem, Vol. 273, Issue 49, 32602-32607, December 4, 1998

Evidence for Contribution by Increased Cytoplasmic Na⁺ to the Insulinotropic Action of PACAP38 in HIT-T15 Cells

From the Department of Medicine, Lund University, S-205 02 Malmö, Sweden

Pituitary adenylate cyclase-activating polypeptide (PACAP) is localized to pancreatic nerve terminals and stimulates insulin secretion. The insulinotropic effect of PACAP38 in insulin-producing HIT-T15 cells is accompanied by increases in cellular cAMP and cytoplasmic Ca²⁺ ([Ca²⁺]_cyt). As also intracellular Na⁺ is important for insulin secretion after glucose and other cAMP forming peptides, we examined the Na⁺ dependence of the insulinotropic effect of PACAP38 in HIT-T15 cells. We found that PACAP38 (100 nM)-induced insulin secretion was diminished by approximately 50% by removal of extracellular Na⁺ (replaced by equimolar N-methyl-D-glucamine). In contrast, removal of Na⁺ did not diminish the formation of cellular cAMP (measured by radioimmunoassay) or the increase in [Ca²⁺]_cyt (measured in FURA-2AM-loaded cell suspensions) induced by PACAP38. Furthermore, PACAP-38 increased the cytoplasmic Na⁺ ([Na⁺]_cyt) in single HIT-T15 cells as measured by the fluorophore sodium-binding benzofran isophthalate. This increase was reduced by removal of extracellular Na⁺ and by inhibition of protein kinase A by H-89. We conclude that the insulinotropic action of PACAP38 is Na⁺-dependent. We propose that PACAP38 opens plasma membrane Na⁺ channels by an action partially mediated by cAMP and protein kinase A, and the subsequent raise in [Na⁺]_cyt elicits insulin secretion by an as yet unsolved mechanism.

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