title: TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death.
abstract: Reactive oxygen species (ROS) can cause pancreatic β-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca2+. Recent studies however revealed that TRPM2 channels can also conduct Zn2+, but the physiological relevance of this property is enigmatic. Given that Zn2+ is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn2+ to affect cell viability. To address this, we used the insulin secreting (INS1) β-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H2O2 activation of TRPM2 channels increases the cytosolic levels of both Ca2+ and Zn2+ and causes apoptotic cell death. Interestingly, chelation of Zn2+ alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn2+ is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn2+ release. Zn2+ release is potentiated by extracellular Ca2+ entry, indicating that Ca2+-induced Zn2+ release leads to apoptosis. Knockout of TRPM2 channels protects mice from β-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca2+-potentiated Zn2+ release underlies ROS-induced β-cell death and Zn2+, rather than Ca2+, plays a primary role in apoptosis.
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Manna
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Munsey
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Nada
authors.initials: N
authors.lastname: Abuarab
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Li
authors.affiliation: †College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
authors.forename: Aruna
authors.initials: A
authors.lastname: Asipu
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Gareth
authors.initials: G
authors.lastname: Howell
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sedo
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Naylor
authors.affiliation: †College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Beech
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Jiang
authors.affiliation: *School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Asipu
authors.initials: A
authors.lastname: Sivaprasadarao
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D050053:TRPM Cation Channels / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D015032:Zinc