Lack of TRPM2 Impaired Insulin Secretion and Glucose Metabolisms in Mice

Uchida, Kunitoshi; Dezaki, Katsuya; Boldbaatar, Damdindorj; Inada, Hitoshi; Shiuchi, Tetsuya; Mori, Yasuo; Yada, Toshihiko; Minokoshi, Yasuhiko; Tominaga, Makoto

doi:10.2337/db10-0276

Cited by 170 publications

(143 citation statements)

References 28 publications

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“…Uchida et al [15] reported that TRPM2 knockout mice exhibit slightly elevated basal insulin, impaired glucose tolerance, but normal fasting blood glucose levels. Zhang et al [17], by contrast, reported that TRPM2 knockout improves glucose tolerance (due to improved insulin sensitivity), but has no effect on basal glucose or insulin levels.…”

Section: Discussionmentioning

confidence: 99%

“…Its activation thus can raise cytosolic Ca 2 + through extracellular entry and lysosomal release. The TRPM2 channel is proposed to play a dual role in β-cell physiology with modest TRPM2-mediated Ca 2 + elevation being implicated in glucose-stimulated insulin secretion [15,16], although the in vivo evidence in TRPM2-knockout mice is somewhat controversial [15,17]. However, strong activation of the channel causes excessive Ca 2 + elevation resulting in β-cell death [9,11,12,14,18].…”

Section: Introductionmentioning

confidence: 99%

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TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

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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 Ca 2 + . Recent studies however revealed that TRPM2 channels can also conduct Zn 2 + , but the physiological relevance of this property is enigmatic. Given that Zn 2 + is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn 2 + 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. H 2 O 2 activation of TRPM2 channels increases the cytosolic levels of both Ca 2 + and Zn 2 + and causes apoptotic cell death. Interestingly, chelation of Zn 2 + alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn 2 + is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn 2 + release. Zn 2 + release is potentiated by extracellular Ca 2 + entry, indicating that Ca 2 + -induced Zn 2 + 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, Ca 2 + -potentiated Zn 2 + release underlies ROS-induced β-cell death and Zn 2 + , rather than Ca 2 + , plays a primary role in apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

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“…These agonists are believed to act on a unique C-terminal pyrophosphatase domain in TRPM2 (Nudix-like domain) (11)(12)(13). Temperature-dependent activation of TRPM2 plays significant roles in cellular functions, including insulin release from pancreatic β cells (10,14). TRPM2 channels can be activated by hydrogen peroxide (H 2 O 2 ) and are reported to be involved in cell death caused by oxidative stress via mechanisms that remain to be clarified (15,16).…”

Section: Calcium | Immune Cellsmentioning

confidence: 99%

Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions

Kashio

Sokabe²,

Shintaku³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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117

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The ability to sense temperature is essential for organism survival and efficient metabolism. Body temperatures profoundly affect many physiological functions, including immunity. Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca 2+ -permeable cation channel expressed in a wide range of immunocytes. TRPM2 is activated by adenosine diphosphate ribose and hydrogen peroxide (H 2 O 2 ), although the activation mechanism by H 2 O 2 is not well understood. Here we report a unique activation mechanism in which H 2 O 2 lowers the temperature threshold for TRPM2 activation, termed “sensitization,” through Met oxidation and adenosine diphosphate ribose production. This sensitization is completely abolished by a single mutation at Met-214, indicating that the temperature threshold of TRPM2 activation is regulated by redox signals that enable channel activity at physiological body temperatures. Loss of TRPM2 attenuates zymosan-evoked macrophage functions, including cytokine release and fever-enhanced phagocytic activity. These findings suggest that redox signals sensitize TRPM2 downstream of NADPH oxidase activity and make TRPM2 active at physiological body temperature, leading to increased cytosolic Ca 2+ concentrations. Our results suggest that TRPM2 sensitization plays important roles in macrophage functions.

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“…On contact with pathogens, phagocytic cells produce reactive oxygen species (ROS); the resulting activation of TRPM2 provides the Ca 2+ influx necessary for cell migration and chemokine production (1). In pancreatic β cells, TRPM2 activity contributes to glucose-evoked insulin secretion; TRPM2 knock-out mice show higher resting blood glucose levels and impaired glucose tolerance (2).…”

mentioning

confidence: 99%

Putative chanzyme activity of TRPM2 cation channel is unrelated to pore gating

Tóth

Iordanov

Csanády

2014

Proc. Natl. Acad. Sci. U.S.A.

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Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ -permeable cation channel expressed in immune cells of phagocytic lineage, pancreatic β cells, and brain neurons and is activated under oxidative stress. TRPM2 activity is required for immune cell activation and insulin secretion and is responsible for postischemic neuronal cell death. TRPM2 is opened by binding of ADP ribose (ADPR) to its C-terminal cytosolic nudix-type motif 9 (NUDT9)-homology (NUDT9-H) domain, which, when expressed in isolation, cleaves ADPR into AMP and ribose-5-phosphate. A suggested coupling of this enzymatic activity to channel gating implied a potentially irreversible gating cycle, which is a unique feature of a small group of channel enzymes known to date. The significance of such a coupling lies in the conceptually distinct pharmacologic strategies for modulating the open probability of channels obeying equilibrium versus nonequilibrium gating mechanisms. Here we examine the potential coupling of TRPM2 enzymatic activity to pore gating. Mutation of several residues proposed to enhance or eliminate NUDT9-H catalytic activity all failed to affect channel gating kinetics. An ADPR analog, α-β-methylene-ADPR (AMPCPR), was shown to be entirely resistant to hydrolysis by NUDT9, but nevertheless supported TRPM2 channel gating, albeit with reduced apparent affinity. The rate of channel deactivation was not slowed but, rather, accelerated in AMPCPR. These findings, as well as detailed analyses of steady-state gating kinetics of single channels recorded in the presence of a range of concentrations of ADPR or AMPCPR, identify TRPM2 as a simple ligand-gated channel that obeys an equilibrium gating mechanism uncoupled from its enzymatic activity.

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Lack of TRPM2 Impaired Insulin Secretion and Glucose Metabolisms in Mice

Cited by 170 publications

References 28 publications

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions

Putative chanzyme activity of TRPM2 cation channel is unrelated to pore gating

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