H2O2-induced Ca2+ influx and its inhibition by N-(p-amylcinnamoyl) anthranilic acid in the β-cells: involvement of TRPM2 channels

Type 2 melastatin‐related transient receptor potential channel (TRPM2), a member of the melastatin‐related TRP (transient receptor potential) subfamily is a Ca2+‐permeable channel activated by hydrogen peroxide (H2O2). We have investigated the role of TRPM2 channels in mediating the H2O2‐induced increase in the cytoplasmic free Ca2+ concentration ([Ca2+]i) in insulin‐secreting cells. In fura‐2 loaded INS‐1E cells, a widely used model of β‐cells, and in human β‐cells, H2O2 increased [Ca2+]i, in the presence of 3 mM glucose, by inducing Ca2+ influx across the plasma membrane. H2O2‐induced Ca2+ influx was not blocked by nimodipine, a blocker of the L‐type voltage‐gated Ca2+ channels nor by 2‐aminoethoxydiphenyl borate, a blocker of several TRP channels and store‐operated channels, but it was completely blocked by N‐(p‐amylcinnamoyl)anthranilic acid (ACA), a potent inhibitor of TRPM2. Adenosine diphosphate phosphate ribose, a specific activator of TRPM2 channel and H2O2, induced inward cation currents that were blocked by ACA. Western blot using antibodies directed to the epitopes on the N‐terminal and on the C‐terminal parts of TRPM2 identified the full length TRPM2 (TRPM2‐L), and the C‐terminally truncated TRPM2 (TRPM2‐S) in human islets. We conclude that functional TRPM2 channels mediate H2O2‐induced Ca2+ entry in β‐cells, a process potently inhibited by ACA.

[1]  M. Tominaga,et al.  Inhibition of the transient receptor potential cation channel TRPM2 by 2‐aminoethoxydiphenyl borate (2‐APB) , 2008, British journal of pharmacology.

[2]  B. Hellman,et al.  Phospholipase A2 Is Important for Glucose Induction of Rhythmic Ca2+ Signals in Pancreatic &bgr; Cells , 2007, Pancreas.

[3]  M. Andersen,et al.  Reactive Oxygen Species as a Signal in Glucose-Stimulated Insulin Secretion , 2007, Diabetes.

[4]  R. Kraft,et al.  N-(p-amylcinnamoyl)anthranilic acid (ACA): a phospholipase A(2) inhibitor and TRP channel blocker. , 2007, Cardiovascular drug reviews.

[5]  J. Eisfeld,et al.  Endogenous ADP-ribose enables calcium-regulated cation currents through TRPM2 channels in neutrophil granulocytes. , 2006, The Biochemical journal.

[6]  J. Schjoerring,et al.  Membrane transport of hydrogen peroxide. , 2006, Biochimica et biophysica acta.

[7]  R. Kraft,et al.  Inhibition of TRPM2 cation channels by N‐(p‐amylcinnamoyl)anthranilic acid , 2006, British journal of pharmacology.

[8]  Haowei Song,et al.  Effects of biological oxidants on the catalytic activity and structure of group VIA phospholipase A2. , 2006, Biochemistry.

[9]  M. Tominaga,et al.  TRPM2 activation by cyclic ADP‐ribose at body temperature is involved in insulin secretion , 2006, The EMBO journal.

[10]  B. A. Miller,et al.  The Role of TRP Channels in Oxidative Stress-induced Cell Death , 2006, The Journal of Membrane Biology.

[11]  C. Grimm,et al.  Block of TRPC5 channels by 2‐aminoethoxydiphenyl borate: a differential, extracellular and voltage‐dependent effect , 2005, British journal of pharmacology.

[12]  B. Stoddard,et al.  Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels* , 2005, Journal of Biological Chemistry.

[13]  C. Östenson,et al.  Ryanodine receptor‐operated activation of TRP‐like channels can trigger critical Ca2+ signaling events in pancreatic β‐cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  A. Randall,et al.  Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[15]  C. D. Benham,et al.  Flufenamic acid is a pH-dependent antagonist of TRPM2 channels , 2004, Neuropharmacology.

[16]  S. Skaper,et al.  TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP‐ribose) polymerase , 2004, British journal of pharmacology.

[17]  S. Theander,et al.  Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. , 2004, Endocrinology.

[18]  G. Schultz,et al.  Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. , 2004, American journal of physiology. Cell physiology.

[19]  J. Cheung,et al.  A Novel TRPM2 Isoform Inhibits Calcium Influx and Susceptibility to Cell Death* , 2003, The Journal of Biological Chemistry.

[20]  J. Gromada,et al.  Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism. , 2003, Biochemical and biophysical research communications.

[21]  H. Westerblad,et al.  Ryanodine receptors of pancreatic β‐cells mediate a distinct context‐dependent signal for insulin secretion , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  H. Matsushime,et al.  Response to ADP-Ribose by Activation of TRPM2 in the CRI-G1 Insulinoma Cell Line , 2003, The Journal of Membrane Biology.

[23]  Lauren Mackenzie,et al.  2‐Aminoethoxydiphenyl borate (2‐APB) is a reliable blocker of store‐operated Ca2+ entry but an inconsistent inhibitor of InsP3‐induced Ca2+ release , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  J. Eisfeld,et al.  Activation of the Cation Channel Long Transient Receptor Potential Channel 2 (LTRPC2) by Hydrogen Peroxide , 2002, The Journal of Biological Chemistry.

[25]  A. Kuznetsov,et al.  TRP genes: candidates for nonselective cation channels and store-operated channels in insulin-secreting cells. , 2002, Diabetes.

[26]  N. Shimizu,et al.  LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. , 2002, Molecular cell.

[27]  A. Perraud,et al.  ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology , 2001, Nature.

[28]  C. Tei,et al.  Diverse effects of hydrogen peroxide on cytosolic Ca2+ homeostasis in rat pancreatic beta-cells. , 2000, Cell structure and function.

[29]  C. Wollheim,et al.  Hydrogen Peroxide Alters Mitochondrial Activation and Insulin Secretion in Pancreatic Beta Cells* , 1999, The Journal of Biological Chemistry.

[30]  P. Herson,et al.  Hydrogen Peroxide Induces Intracellular Calcium Overload by Activation of a Non-selective Cation Channel in an Insulin-secreting Cell Line* , 1999, The Journal of Biological Chemistry.

[31]  F. Lang,et al.  Interference of H2O2 with stimulus‐secretion coupling in mouse pancreatic β‐cells , 1999, The Journal of physiology.

[32]  B. Ahrén,et al.  Ca2+-independent phospholipase A2 contributes to the insulinotropic action of cholecystokinin-8 in rat islets: dissociation from the mechanism of carbachol. , 1998, Diabetes.

[33]  B. Hering,et al.  Assessment of intracellular insulin content during all steps of human islet isolation procedure. , 1998, Cell transplantation.

[34]  E. Neher,et al.  The use of fura-2 for estimating ca buffers and ca fluxes , 1995, Neuropharmacology.

[35]  Stephan Frings,et al.  Profoundly different calcium permeation and blockage determine the specific function of distinct cyclic nucleotide-gated channels , 1995, Neuron.

[36]  B. Wolf,et al.  Inhibition of phospholipase A2 and insulin secretion in pancreatic islets. , 1992, Biochimica et biophysica acta.

[37]  P. Lacy,et al.  Automated Islet Isolation From Human Pancreas , 1989, Diabetes.