The Human Transient Receptor Potential Melastatin 2 Ion Channel Modulates ROS Through Nrf2

Lei Bao, Fernanda Festa, Christopher S. Freet, John P. Lee, Iwona M. Hirschler-Laszkiewicz, Shu jen Chen, Kerry A. Keefer, Hong Gang Wang, Andrew D. Patterson, Joseph Y. Cheung, Barbara A. Miller

Research output: Contribution to journalArticle

Abstract

Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential role in protecting cell viability through modulation of oxidative stress. TRPM2 is highly expressed in cancer. When TRPM2 is inhibited, mitochondria are dysfunctional, ROS levels are increased, and cell viability is reduced. Here, the importance of NF-E2-related factor (Nrf2) in TRPM2-mediated suppression of oxidant stress was explored. In TRPM2 depleted cells, antioxidant cofactors glutathione, NADPH, and NADH were significantly reduced. Cytoplasmic and nuclear expression of Nrf2 and of IQGAP1, a modulator of Nrf2 stability regulated by intracellular calcium, were decreased. Antioxidant enzymes transcriptionally regulated by Nrf2 and involved in GSH, NADPH, and NADH generation were significantly lower including PRX1 and PRX3, GPX4, GSTP1, GCLC, and MTHFD2. The glutamine pathway leading to GSH production was suppressed, and ATP and GTP levels were impaired. Reconstitution with wild type TRPM2 or Nrf2, but not TRPM2 pore mutant E960D, rescued expression of enzymes downstream of Nrf2 and restored GSH and GTP. Cell viability, ROS, NADPH, NADH, and ATP levels were fully rescued by TRPM2 and partially by Nrf2. These data show that TRPM2 maintains cell survival following oxidative stress through modulation of antioxidant pathways and cofactors regulated by Nrf2.

Original languageEnglish (US)
Article number14132
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Transient Receptor Potential Channels
Ion Channels
Cell Survival
NADP
NAD
Antioxidants
Guanosine Triphosphate
Oxidative Stress
Adenosine Triphosphate
Enzymes
Glutamine
Oxidants
Glutathione
Mitochondria
Calcium

All Science Journal Classification (ASJC) codes

  • General

Cite this

Bao, Lei ; Festa, Fernanda ; Freet, Christopher S. ; Lee, John P. ; Hirschler-Laszkiewicz, Iwona M. ; Chen, Shu jen ; Keefer, Kerry A. ; Wang, Hong Gang ; Patterson, Andrew D. ; Cheung, Joseph Y. ; Miller, Barbara A. / The Human Transient Receptor Potential Melastatin 2 Ion Channel Modulates ROS Through Nrf2. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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author = "Lei Bao and Fernanda Festa and Freet, {Christopher S.} and Lee, {John P.} and Hirschler-Laszkiewicz, {Iwona M.} and Chen, {Shu jen} and Keefer, {Kerry A.} and Wang, {Hong Gang} and Patterson, {Andrew D.} and Cheung, {Joseph Y.} and Miller, {Barbara A.}",
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The Human Transient Receptor Potential Melastatin 2 Ion Channel Modulates ROS Through Nrf2. / Bao, Lei; Festa, Fernanda; Freet, Christopher S.; Lee, John P.; Hirschler-Laszkiewicz, Iwona M.; Chen, Shu jen; Keefer, Kerry A.; Wang, Hong Gang; Patterson, Andrew D.; Cheung, Joseph Y.; Miller, Barbara A.

In: Scientific reports, Vol. 9, No. 1, 14132, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Bao, Lei

AU - Festa, Fernanda

AU - Freet, Christopher S.

AU - Lee, John P.

AU - Hirschler-Laszkiewicz, Iwona M.

AU - Chen, Shu jen

AU - Keefer, Kerry A.

AU - Wang, Hong Gang

AU - Patterson, Andrew D.

AU - Cheung, Joseph Y.

AU - Miller, Barbara A.

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