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.

Full text available as:

	(Accepted Manuscript) Due to publisher licensing restrictions, this file is not available for public download
Preview	PDF (Version of Record) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader Download (4MB) | Preview
	(Not Set) Due to publisher licensing restrictions, this file is not available for public download

DOI (Digital Object Identifier) Link:	https://doi.org/10.1074/jbc.M115.671248
Google Scholar:	Look up in Google Scholar

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.

Item Type:	Journal Item
Copyright Holders:	2015 The American Society for Biochemistry and Molecular Biology
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/School:	Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID:	44168
Depositing User:	Katja Rietdorf
Date Deposited:	25 Aug 2015 09:43
Last Modified:	02 May 2018 14:13
URI:	http://oro.open.ac.uk/id/eprint/44168
Share this page:

Metrics

Altmetrics from Altmetric	Citations from Dimensions

Actions (login may be required)

RDF+XMLBibTeXRIOXX2 XMLRDF+N-TriplesJSONDublin CoreAtomSimple MetadataReferMETSHTML CitationASCII CitationRefMan RIS Format (UTF-8)OpenURL ContextObjectEndNoteMODSOpenURL ContextObject in SpanMPEG-21 DIDLEP3 XMLRefMan RIS FormatRDF+N3