title: Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells.
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.
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, aarredouani@qf.org.qa.
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Arredouani
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Margarida
authors.initials: M
authors.lastname: Ruas
authors.affiliation: the Centre des Sciences du Gout et de l'Alimentation, Equipe 5, 9E Boulevard Jeanne d'Arc 21000 Dijon, France.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Collins
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Raman
authors.initials: R
authors.lastname: Parkesh
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Frederick
authors.initials: F
authors.lastname: Clough
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Toby
authors.initials: T
authors.lastname: Pillinger
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Coltart
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Katja
authors.initials: K
authors.lastname: Rietdorf
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Royle
authors.affiliation: the Nuffield Department of Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Johnson
authors.affiliation: the The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
authors.affiliation: the The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: the The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Sones
authors.affiliation: the Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom.
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Morgan
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lewis
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Kai-Ting
authors.initials: KT
authors.lastname: Chuang
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tunn
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Gadea
authors.affiliation: The Mary Lyon Centre, Medical Research Council Harwell, Oxfordshire OX11 0RD, United Kingdom.
authors.forename: Lydia
authors.initials: L
authors.lastname: Teboul
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Heister
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Tynan
authors.affiliation: the Centre des Sciences du Gout et de l'Alimentation, Equipe 5, 9E Boulevard Jeanne d'Arc 21000 Dijon, France.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Bellomo
authors.affiliation: the 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.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: the The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, john.parrington@pharm.ox.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Parrington
authors.affiliation: From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, antony.galione@pharm.ox.ac.uk.
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D000097903:Two-Pore Channels
chemical_list: D002118:Calcium; D015220:Calcium Channels; D005947:Glucose; D007328:Insulin; D009249:NADP; C546784:TPCN1 protein, mouse; D000097903:Two-Pore Channels; C546785:TPCN2 protein, mouse; C024376:NAADP
keywords: TPC1; TPC2; diabetes; endosome; insulin; lysosome; nicotinic acid adenine dinucleotide phosphate (NAADP)