Arredouani, Abdelilah, Ruas, Margarida, Collins, Stephan C, Parkesh, Raman, Clough, Frederick, Pillinger, Toby, Coltart, George, Rietdorf, Katja, Royle, Andrew, Johnson, Paul, Braun, Matthias, Zhang, Quan, Sones, William, Shimomura, Kenju, Morgan, Anthony J, Lewis, Alexander M, Chuang, Kai-Ting, Tunn, Ruth, Gadea, Joaquin, Teboul, Lydia, Heister, Paula M, Tynan, Patricia W, Bellomo, Elisa A, Rutter, Guy A, Rorsman, Patrik, Churchill, Grant C, Parrington, John and Galione, Antony (2015) Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells. The Journal of Biological Chemistry, 290 (35), 21376-92. (doi:10.1074/jbc.M115.671248).
Abstract
Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca(2+) action potentials due to the activation of voltage-dependent Ca(2+) channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca(2+) release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic β cells. NAADP-regulated Ca(2+) release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca(2+) from the endolysosomal system, resulting in localized Ca(2+) signals. We show here that NAADP-mediated Ca(2+) release from endolysosomal Ca(2+) stores activates inward membrane currents and depolarizes the β cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during stimulus-response coupling. Selective pharmacological inhibition of NAADP-evoked Ca(2+) release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca(2+) signals, and insulin secretion. Our findings implicate NAADP-evoked Ca(2+) release from acidic Ca(2+) storage organelles in stimulus-secretion coupling in β cells.
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