The Poly(ADP-ribose) Polymerase PARP-1 Is Required for Oxidative Stress-induced TRPM2 Activation in Lymphocytes

Buelow, Ben; Song, Yumei; Scharenberg, Andrew M.

doi:10.1074/jbc.m802673200

Cited by 133 publications

(106 citation statements)

References 102 publications

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“…Although TRPM2 is activated by ROS and is involved in cell death after oxidative stress (15,16), the activation mechanisms involved are unclear (17)(18)(19)(20). The primary activator of TRPM2 is thought to be ADPR, with most previous studies suggesting that the release of ADPR from the nucleus and mitochondria plays a primary role in TRPM2 activation by H 2 O 2 (17)(18)(19), although one study has reported that H 2 O 2 acts on TRPM2 directly (20).…”

Section: Discussionmentioning

confidence: 99%

“…Most previous studies have suggested that TRPM2 activation by H 2 O 2 is caused by ADPR release from intracellular organelles (17)(18)(19). To test this possibility, we evaluated the effects of H 2 O 2 in inside-out single-channel recordings in which intracellular components are absent.…”

Section: Resultsmentioning

confidence: 99%

“…The primary activator of TRPM2 is thought to be ADPR, with most previous studies suggesting that the release of ADPR from the nucleus and mitochondria plays a primary role in TRPM2 activation by H 2 O 2 (17)(18)(19), although one study has reported that H 2 O 2 acts on TRPM2 directly (20). We show here that H 2 O 2 can sensitize TRPM2 in the absence of these organelles and activate it at physiological temperatures in a membrane-delimited manner by reducing the temperature threshold for activation.…”

Section: Discussionmentioning

confidence: 99%

“…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). ADPR released from intracellular organelles, such as the nucleus and mitochondria, may play a primary role in TRPM2 activation by H 2 O 2 (17)(18)(19), although one report suggests involvement of an ADPR-independent activation mechanism (20). H 2 O 2 , a reactive oxygen species (ROS) produced by NADPH oxidase (Nox), is crucial for microorganism removal, given that defects in H 2 O 2 production lead to persistent infections (21).…”

Section: Calcium | Immune Cellsmentioning

confidence: 99%

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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.

151

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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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Calcium | Immune Cellsmentioning

confidence: 99%

See 2 more Smart Citations

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.

151

117

View full text Add to dashboard Cite

show abstract

“…[19][20][21] The male-specific overactivation of PARP-1 in ischemic cell death is particularly relevant because PARP-1-generated adenosine-5 0 -diphosphoribose (ADPr) directly activates TRPM2 channels after exposure to exogenous oxidants. 22,23 Transient receptor potential M2 channels are the only known ion channels to be directly activated by intracellular ADPr, therefore we hypothesize that TRPM2 is a downstream mediator of PARP-1-induced cell death. Several studies report that PARP inhibitors, and deletion of the PARP-1 gene, provides protection in a sexually dimorphic manner, protecting male, but not female, brain.…”

Section: Introductionmentioning

confidence: 93%

Androgen and PARP-1 Regulation of TRPM2 Channels after Ischemic Injury

Shimizu

Macey

Quillinan

et al. 2013

J Cereb Blood Flow Metab

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The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.

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Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

Pall

2009

General, Applied and Systems Toxicology

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Cases of multiple chemical sensitivity (MCS) are initiated by exposure to organic solvents and three classes of pesticides. Each of these can act indirectly to increase NMDA activity and the toxic effects of members of each of these classes can be lowered by using NMDA antagonists. Other chemicals, mercury, H 2 S and CO exposure may also initiate cases of MCS and have toxic responses mediated through increased NMDA activity. Thus each of these types of chemicals appears to act as a toxicant through increased NMDA activity. Six additional types of evidence suggest roles for elevated NMDA activity in MCS, suggesting that this response is involved, not only in MCS case initiation, but also in response to low‐level chemicals in those who are already sensitive. The inference that chemicals act as toxicants in MCS is confirmed by three genetic studies showing that five genes that encode enzymes that metabolize these chemicals act to determine MCS susceptibility. The chronic nature of MCS is thought to be produced by a local biochemical vicious cycle mechanism, the NO/ONOO − cycle, which is initiated by nitric oxide acting through its oxidant product peroxynitrite, which are both produced in MCS in response to excessive NMDA activity. Cycle elements, including NMDA activity, intracellular calcium, nitric oxide and peroxynitrite are thought to interact with other mechanisms, including neural sensitization in the brain and neurogenic inflammation in peripheral tissues to produce the high‐level chemical sensitivity that is the hallmark of MCS. This complex model of MCS is supported by the following types of observations: MCS correlates in the chronic phase of illness, extensive animal model studies implicating almost all NO/ONOO − cycle elements, clinical trial data in the related illnesses chronic fatigue syndrome and fibromyalgia, and a variety of objectively measurable responses to low‐level chemical exposure in MCS patients, responses that should be further studied as possible specific biomarker tests for MCS. While plausible mechanisms are proposed for the generation of both shared and specific symptoms and signs in MCS, there are little data on whether these mechanisms are actually involved in generating these symptoms and signs in MCS. Previous claims that MCS is produced by some sort of psychogenic mechanism have multiple flaws and are inconsistent with the various types of evidence discussed above. Several areas of research are discussed in which the author argues that research will be richly rewarded.

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The Poly(ADP-ribose) Polymerase PARP-1 Is Required for Oxidative Stress-induced TRPM2 Activation in Lymphocytes

Cited by 133 publications

References 102 publications

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

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

Androgen and PARP-1 Regulation of TRPM2 Channels after Ischemic Injury

Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

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