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Role of Phosphoinositide Signaling in the Control of Insulin Exocytosis

Department of Cell Biology and Morphology, University of Lausanne (L.W., R.R.), Lausanne 1005, Switzerland; Department of Biochemistry, University of Wisconsin (R.R.L.G., T.F.J.M.), Madison, Wisconsin 53706; and Neurotransmission and Neuroendocrine Secretion, Centre National de la Recherche Scientifique, Unit 2356 (N.V., M.-F.B.), Strasbourg 67084, France

Address all correspondence and requests for reprints to: Dr. Romano Regazzi, Department of Cell Biology and Morphology, rue du Bugnon 9, 1005 Lausanne, Switzerland. E-mail: romano.regazzi{at}unil.ch.

Phosphoinositides (PI) are important signaling molecules involved in the regulation of vesicular trafficking. We found that phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-biphosphate [PI(4,5)P₂] increase the secretory response triggered by 10 µM Ca²⁺ in streptolysin-O-permeabilized insulin-secreting INS-1E cells. In addition, nutrient-induced exocytosis was diminished in intact cells expressing constructs that sequester PI(4,5)P₂ and in cells transfected with constructs that reduce by RNA interference the level of two enzymes involved in PI(4,5)P₂ production, type III PI4-kinase ß and type I phosphatidylinositol 4-bisphosphate 5-kinase-. To clarify the mechanism of action of PI, we investigated the involvement in the regulation of insulin exocytosis of three potential PI targets, phospholipase D1, the Ca²⁺-dependent activator protein for secretion 1, and Munc18-interacting protein 1. Transfection of insulin-secreting cells with plasmids that direct the synthesis of small interfering RNAs capable of reducing the endogenous levels of these proteins inhibited hormone release elicited by glucose- and cAMP-elevating agents without affecting basal release. Our data indicate that the production of PI(4,5)P₂ is necessary for proper control of ß-cell secretion and suggest that at least part of the effect of PI on insulin exocytosis could be exerted through the activation of phospholipase D1, Ca²⁺-dependent activator protein for secretion 1, and Munc18-interacting protein 1.

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