Nicotinic acid adenine dinucleotide phosphate (NAADP) and endolysosomal two-pore channels modulate membrane excitability and stimulus-secretion coupling in mouse pancreatic β cells

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.