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The role of TRP channels in oxidative stress-induced cell death
1The Department of Pediatrics, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, 17033, USA. bmiller3@psu.edu
Abstract:
The transient receptor potential (TRP) protein superfamily is a diverse group of voltage-independent calcium-permeable cation channels expressed in mammalian cells. These channels have been divided into six subfamilies, and two of them, TRPC and TRPM, have members that are widely expressed and activated by oxidative stress. TRPC3 and TRPC4 are activated by oxidants, which induce Na(+) and Ca(2+) entry into cells through mechanisms that are dependent on phospholipase C. TRPM2 is activated by oxidative stress or TNFalpha, and the mechanism involves production of ADP-ribose, which binds to an ADP-ribose binding cleft in the TRPM2 C-terminus. Treatment of HEK 293T cells expressing TRPM2 with H(2)O(2) resulted in Ca(2+) influx and increased susceptibility to cell death, whereas coexpression of the dominant negative isoform TRPM2-S suppressed H(2)O(2)-induced Ca(2+) influx, the increase in [Ca(2+)](i), and onset of apoptosis. U937-ecoR monocytic cells expressing increased levels of TRPM2 also exhibited significantly increased [Ca(2+)](i) and increased apoptosis after treatment with H(2)O(2) or TNFalpha. A dramatic increase in caspase 8, 9, 3, 7, and PARP cleavage was observed in TRPM2-expressing cells, demonstrating a downstream mechanism through which cell death is mediated. Inhibition of endogenous TRPM2 function through three approaches, depletion of TRPM2 by RNA interference, blockade of the increase in [Ca(2+)](i) through TRPM2 by calcium chelation, or expression of the dominant negative splice variant TRPM2-S protected cell viability. H(2)O(2) and amyloid beta-peptide also induced cell death in primary cultures of rat striatal cells, which endogenously express TRPM2. TRPM7 is activated by reactive oxygen species/nitrogen species, resulting in cation conductance and anoxic neuronal cell death, which is rescued by suppression of TRPM7 expression. TRPM2 and TRPM7 channels are physiologically important in oxidative stress-induced cell death.
Insights
Transient Receptor Potential melastatin 2 (TRPM2) and TRPM7 channels are crucial in oxidative stress-induced cell death. Inhibiting TRPM2 function protects cells from damage, highlighting their physiological importance.
Area of Science:
- Molecular Biology
- Cell Biology
- Neuroscience
Background:
- Transient Receptor Potential (TRP) channels are a superfamily of ion channels.
- TRP channels are involved in various cellular processes, including calcium permeability.
- TRPC and TRPM subfamilies are activated by oxidative stress.
Purpose of the Study:
- To investigate the role of TRPM2 and TRPM7 channels in oxidative stress-induced cell death.
- To elucidate the mechanisms by which TRPM2 activation leads to cell death.
- To evaluate the therapeutic potential of inhibiting TRPM2 function.
Main Methods:
- HEK 293T and U937-ecoR cells expressing TRPM2 were treated with hydrogen peroxide (H2O2) or TNFalpha.
- Dominant-negative TRPM2-S isoform and RNA interference were used to inhibit TRPM2 function.
- Primary cultures of rat striatal cells expressing endogenous TRPM2 were treated with H2O2 and amyloid beta-peptide.
- Caspase activation and cleavage of PARP were assessed.
- TRPM7 expression was suppressed to evaluate its role in cell death.
Main Results:
- H2O2 treatment induced Ca(2+) influx and apoptosis in TRPM2-expressing cells.
- Inhibition of TRPM2 function, via dominant-negative variants or RNA interference, protected cells from H2O2-induced death.
- TRPM2 activation by H2O2 or TNFalpha led to increased intracellular calcium and apoptosis in monocytic cells.
- TRPM2-expressing cells showed increased caspase activation and PARP cleavage.
- TRPM7 activation by reactive oxygen/nitrogen species caused neuronal cell death, which was rescued by TRPM7 suppression.
- TRPM2 and TRPM7 channels are physiologically important in oxidative stress-induced cell death.
Conclusions:
- TRPM2 and TRPM7 channels play significant roles in oxidative stress-induced cell death.
- TRPM2-mediated calcium influx and subsequent caspase activation are key mechanisms in oxidative stress-induced apoptosis.
- Inhibiting TRPM2 function offers a potential strategy for protecting cells against oxidative stress-related damage.
- TRPM2 and TRPM7 are critical targets for understanding and potentially treating conditions involving oxidative stress and neuronal cell death.
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