The Role of TRP Channels in Oxidative Stress-induced Cell Death

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.

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

“…2,[7][8][9] Transient receptor potential M2 (TRPM2) channels were initially identified and extensively characterized by our group, 7,8,10,11 and demonstrated to contribute to oxidative stress-induced cell death. Indeed, the most well-characterized role for TRPM2 is as an executioner of cell death after oxidative stress, leading to excessive Ca 2 þ influx and consequent cell death (For review, see 1,2,9,12,13 ). This observation provided a strong rationale to hypothesize that TRPM2 channels have a significant role in a variety of neurodegenerative diseases whose etiologies involve oxidative stress, including ischemic stroke.…”

Identification of microRNAs associated with hyperthermia-induced cellular stress response

“…A few well-characterized stressors include hyperthermia, hypoxia, ionizing and non-ionizing radiation, ATP depletion, oxidative stress, and pathogenic stimuli (Schreck et al 1992;Feder and Hofmann 1999;Kabakov et al 2002;Kultz 2005;Diller 2006;Miller 2006;Millenbaugh et al 2008). At the cellular level, stressors can inflict strain on intracellular biomolecules (e.g., lipids, proteins, and DNA, and if such strain is appreciable, these biomolecules can undergo structural modifications that can preclude them from functioning properly.…”

Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes

“…Mammalian TRP channels are divided into six subfamilies, and the TRPC (canonical) family in particular has been implicated in contributing to cellular Ca 2ϩ homeostasis (9,14,23,24,43). There are seven members of the TRPC family (TRPC1-7), six of which (TRPC1-6) have been shown, at least by RT-PCR, to be present in the heart (9).…”

“…There are seven members of the TRPC family (TRPC1-7), six of which (TRPC1-6) have been shown, at least by RT-PCR, to be present in the heart (9). Structurally, TRP channels consist of six transmembrane domains containing a putative Ca 2ϩ pore region between the fifth and sixth domains; TRPC channels have ankyrin repeat domains in their NH 2 terminus, which may mediate protein-protein interactions (23). Prototypical activation of TRPC channels occurs in response to agonist stimulation, resulting in the generation of diacylglycerol and inositol 1,4,5-trisphosphate (IP 3 ).…”

“…Subsequent activation of the endo/sarcoplasmic reticulum IP 3 receptor can mediate depletion of Ca 2ϩ from internal stores, thereby triggering Ca 2ϩ entry across the sarcolemma via TRPCs. Independent of store depletion, TRPC activity can be regulated by an increase in diacylglycerol; alternatively, IP 3 receptor bound to IP 3 may activate TRPC via direct interaction (23).…”