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J Biol Chem. 2015 Aug 28;290(35):21376-92. doi: 10.1074/jbc.M115.671248. Epub 2015 Jul 7.

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells.

Author information

  • 1From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, aarredouani@qf.org.qa.
  • 2From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
  • 3the Centre des Sciences du Gout et de l'Alimentation, Equipe 5, 9E Boulevard Jeanne d'Arc 21000 Dijon, France.
  • 4the Nuffield Department of Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom.
  • 5the The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.
  • 6the Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom.
  • 7The Mary Lyon Centre, Medical Research Council Harwell, Oxfordshire OX11 0RD, United Kingdom.
  • 8the Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Medicine, Imperial College London, Hammersmith Hospital, du Cane Road, London W12 0NN, United Kingdom, and.
  • 9From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, john.parrington@pharm.ox.ac.uk.
  • 10From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, antony.galione@pharm.ox.ac.uk.

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.

KEYWORDS:

TPC1; TPC2; diabetes; endosome; insulin; lysosome; nicotinic acid adenine dinucleotide phosphate (NAADP)

PMID:
26152717
PMCID:
PMC4571866
DOI:
10.1074/jbc.M115.671248
[PubMed - indexed for MEDLINE]
Free PMC Article
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