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.
Highlights
two-pore channels (TPCs) are regulated by nicotinic acid adenine dinucleotide phosphate (NAADP) and other factors
We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2؉ release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic  cells
2 5 μm Glucose and Tolbutamide-evoked Ca2ϩ Responses Are Reduced in Isolated Pancreatic  Cells from Tpcn2Ϫ/Ϫ Mice—We examined the effects of infusing NAADP (100 nM) into mouse pancreatic  cells from age, sex, and backgroundmatched wild-type and Tpcn2Ϫ/Ϫ mice via the patch pipette during standard whole-cell recordings while simultaneously measuring intracellular Ca2ϩ concentrations and inward membrane currents
Summary
TPCs are regulated by NAADP and other factors. Results: NAADP-induced Ca2ϩ release from acidic stores evokes depolarizing currents in pancreatic  cells. Inhibition of NAADP signaling or TPC knock out attenuates Ca2ϩ signaling and insulin secretion. Conclusion: NAADP-evoked Ca2ϩ release enhances  cell excitability and insulin secretion in response to glucose or sulfonylureas. Significance: NAADP signaling pathways offer novel therapeutic targets for diabetes treatment. Pancreatic  cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca2؉ action potentials due to the activation of voltage-dependent Ca2؉
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