A Critical Role of TRPM2 in Neuronal Cell Death by Hydrogen Peroxide

Kaneko, Shuji; Kawakami, Seiko; Hara, Yuji; Wakamori, Minoru; Itoh, Etsuko; Minami, Toshiyuki; Takada, Youichiro; Kume, Toshiaki; Katsuki, Hiroshi; Mori, Yasuo; Akaike, Akinori

doi:10.1254/jphs.fp0060128

Cited by 196 publications

(160 citation statements)

References 35 publications

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“…TRPM2 knock-out mice are protected against this infiltration and show reduced inflammation in a mouse model of colitis ulcerosa [131]. Neurons also express TRPM2 where it may be involved in H 2 O 2 -induced neuronal death [132,133].…”

Section: Redox Activation Of Trp Channels In Cell Deathmentioning

confidence: 99%

Redox regulation of calcium ion channels: Chemical and physiological aspects

et al. 2011

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a b s t r a c tReactive oxygen species (ROS) are increasingly recognized as second messengers in many cellular processes. While high concentrations of oxidants damage proteins, lipids and DNA, ultimately resulting in cell death, selective and reversible oxidation of key residues in proteins is a physiological mechanism that can transiently alter their activity and function. Defects in ROS producing enzymes cause disturbed immune response and disease.Changes in the intracellular free Ca 2+ concentration are key triggers for diverse cellular functions. Ca 2+ homeostasis thus needs to be precisely tuned by channels, pumps, transporters and cellular buffering systems. Alterations of these key regulatory proteins by reversible or irreversible oxidation alter the physiological outcome following cell stimulation. It is therefore necessary to understand which proteins are regulated and if this regulation is relevant in a physiological-and/or pathophysiological context. Because ROS are inherently difficult to identify and to measure, we first review basic oxygen redox chemistry and methods of ROS detection with special emphasis on electron paramagnetic resonance (EPR) spectroscopy. We then focus on the present knowledge of redox regulation of Ca 2+ permeable ion channels such as voltage-gated (CaV) Ca 2+ channels, transient receptor potential (TRP) channels and Orai channels.© 2011 Elsevier Ltd. All rights reserved. Basic redox chemistry of oxygenMany chemical processes are linked to the exchange of electrons between two or more molecular entities. The transfer of one (or more) electron(s) is associated with oxidation (loss of electron) and reduction (gain of electron) of the components. Such reactions are also known as redox reactions. The processes of reactive oxygen species (ROS) formation and elimination are exclusively of redox nature.Molecular oxygen is the precursor of all ROS. It contains two unpaired electrons in separate (antibonding) orbitals in its outer electron sphere and is thus, by definition, a radical. Radicals have at least one unpaired electron in their orbital system and usually show high reactivity; transition metal ions also may have unpaired electrons, but are not called radicals. Although having radical character, molecular oxygen is chemically rather inert (luckily!), because high * Corresponding authors at: Institut für Biophysik, Gebäude 58, Universität des Saarlandes, D-66421 Homburg/Saar, Germany. Tel.: +49 6841 1626453; fax: +49 6841 1626060.E-mail addresses: ivan.bogeski@uks.eu (I. Bogeski), barbara.niemeyer@uks.eu (B.A. Niemeyer).

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Section: Redox Activation Of Trp Channels In Cell Deathmentioning

confidence: 99%

Redox regulation of calcium ion channels: Chemical and physiological aspects

et al. 2011

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“…H 2 O 2 and cADPR have been proposed to potentiate the effects of ADPR at lower concentrations and to gate the TRPM2 channel directly at higher concentrations 15 . It has been suggested that H 2 O 2 -activated Ca 2+ influx through TRPM2 mediates pathophysiological cell death 14,17 . However, with regard to normal physiological cellular responses, the importance of H 2 O 2 -activated Ca 2+ influx remains to be elucidated.…”

mentioning

confidence: 99%

TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

Yamamoto

Shimizu

Kiyonaka

et al. 2008

Nat Med

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548

552

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Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca 2+ -permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H 2 O 2 ) evokes Ca 2+ influx through TRPM2 to activate Ca 2+ -dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-κB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H 2 O 2 -induced Ca 2+ influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca 2+ influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.

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“…We have now extended this genotyping analysis to TRPM2. TRPM2 channels are highly abundant in immune cells, in insulin-secreting cells, and in the brain, where they are found in microglia and neuronal cells (8)(9)(10)(11). TRPM2 belongs to the transient receptor potential (TRP) superfamily, a group of cation channels that are expressed in virtually all tissue and cell types and are involved in various cellular functions, in the most part related to Ca 2ϩ signaling.…”

mentioning

confidence: 99%

“…TRPM2 has been implicated in cell death induced by oxidants (11,16). The presence of low Mg 2ϩ and high transition metals in the Western Pacific ALS and PD foci create conditions of increased oxidative stress (6).…”

mentioning

confidence: 99%

Altered functional properties of a TRPM2 variant in Guamanian ALS and PD

Hermosura

Cui²,

Go³

et al. 2008

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

114

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Two related neurodegenerative disorders, Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD), originally occurred at a high incidence on Guam, in the Kii peninsula of Japan, and in southern West New Guinea more than 50 years ago. These three foci shared a unique mineral environment characterized by the presence of severely low levels of Ca 2؉ and Mg 2؉ , coupled with high levels of bioavailable transition metals in the soil and drinking water. Epidemiological studies suggest that genetic factors also contribute to the etiology of these disorders. Here, we report that a variant of the transient receptor potential melastatin 2 (TRPM2) gene may confer susceptibility to these diseases. TRPM2 encodes a calciumpermeable cation channel highly expressed in the brain that has been implicated in mediating cell death induced by oxidants. We found a heterozygous variant of TRPM2 in a subset of Guamanian ALS (ALS-G) and PD (PD-G) cases. This variant, TRPM2 P1018L , produces a missense change in the channel protein whereby proline 1018 (Pro 1018 ) is replaced by leucine (Leu 1018 ). Functional studies revealed that, unlike WT TRPM2, P1018L channels inactivate. Our results suggest that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function and that its disruption may, under certain conditions, contribute to disease states.calcium ͉ neurodegeneration ͉ oxidative stress ͉ channelopathy ͉ gene environment

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A Critical Role of TRPM2 in Neuronal Cell Death by Hydrogen Peroxide

Cited by 196 publications

References 35 publications

Redox regulation of calcium ion channels: Chemical and physiological aspects

Redox regulation of calcium ion channels: Chemical and physiological aspects

TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

Altered functional properties of a TRPM2 variant in Guamanian ALS and PD

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