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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).
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.
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About
- Item ORO ID
- 44168
- Item Type
- Journal Item
- ISSN
- 1083-351X
- Project Funding Details
-
Funded Project Name Project ID Funding Body Not Set Not Set Wellcome Trust Not Set Not Set MRC Not Set Not Set The Royal Society - Keywords
- diabetes; endosome; insulin; lysosome; nicotinic acid adenine dinucleotide phosphate (NAADP); TPC1; TPC2
- Academic Unit or School
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Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM) - Copyright Holders
- © 2015 The American Society for Biochemistry and Molecular Biology
- Depositing User
- Katja Rietdorf