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

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. Journal of Biological Chemistry, 290(35) pp. 21376–21392.

DOI: https://doi.org/10.1074/jbc.M115.671248

Abstract

Pancreatic beta cells are electrically excitable, and respond to elevated glucose concentrations with bursts of Ca²⁺ action potentials due to the activation of voltage-dependent Ca²⁺ channels (VDCCs) which leads to the exocytosis of insulin granules. We have examined the possible role of NAADP-mediated Ca²⁺ release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic beta cells. NAADP-regulated Ca²⁺ release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca²⁺ from the endo-lysosomal system, resulting in localized Ca²⁺ signals. We show here that NAADP-mediated Ca²⁺ release from endolysosomal Ca²⁺ stores activates inward membrane currents and depolarizes the beta 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 Ca²⁺ release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulphonylurea-induced membrane currents, depolarization, cytoplasmic Ca²⁺ signals and insulin secretion. Our findings implicate NAADP-evoked Ca²⁺ release from acidic Ca²⁺ storage organelles in stimulus-secretion coupling in beta cells.

Viewing alternatives

Metrics

Item Actions

Export

You can export this page using these formats Digital Object Identifier - DOI