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

Abdelilah Arredouani, Margarida Ruas, Stephan C. Collins, Raman Parkesh, Frederick Clough, Toby Pillinger, George Coltart, Katja Rietdorf, Andrew Royle, Paul Johnson, Matthias Braun, Quan Zhang, William Sones, Kenju Shimomura, Anthony J. Morgan, Alexander M. Lewis, Kai Ting Chuang, Ruth Tunn, Joaquin Gadea, Lydia TeboulPaula M. Heister, Patricia W. Tynan, Elisa A. Bellomo, Guy A. Rutter, Patrik Rorsman, Grant C. Churchill, John Parrington, Antony Galione

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27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21376-21392
Number of pages17
JournalJournal of Biological Chemistry
Volume290
Issue number35
DOIs
Publication statusPublished - 28 Aug 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Arredouani, A., Ruas, M., Collins, S. C., Parkesh, R., Clough, F., Pillinger, T., Coltart, G., Rietdorf, K., Royle, A., Johnson, P., Braun, M., Zhang, Q., Sones, W., Shimomura, K., Morgan, A. J., Lewis, A. M., Chuang, K. T., Tunn, R., Gadea, J., ... Galione, A. (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), 21376-21392. https://doi.org/10.1074/jbc.M115.671248