TRP Channels as Mediators of Oxidative Stress

Abstract

The transient receptor potential (TRP) protein superfamily is a diverse group of cation-permeable channels expressed in mammalian cells, which is divided into six subfamilies based on sequence identity. Three subfamilies have members with roles in oxidative stress: the TRPC subfamily characterized by receptor operated calcium entry channels; the TRPM subfamily with a number of members involved in cell proliferation and death; and the TRPV subfamily which is activated by chemical, mechanical, and physical stimuli. The TRPC members TRPC3 and TRPC4 can serve as subunits of a redox-sensitive ion channel in native aortic endothelial cells. The TRPM family member TRPM2 has a number of physiologic isoforms expressed in many cell types and responds to stimuli including oxidative stress, TNFα, and β-amyloid peptide. The important role of TRPM2 isoforms in cell proliferation and oxidant-induced cell death has been well established using divergent cell systems and techniques including overexpression, channel depletion or inhibition, and calcium chelation. TRPM7 has been shown to be involved in Ca(2+) influx and anoxic cell death in cortical neurons. In these cells and in B cells, precise expression of TRPM7 is necessary for cell survival. TRPV1 is involved in oxidant stress-induced pain and in neuronal injury, contributing to diabetic sensory neuropathy. Future studies will likely identify additional channels involved in oxidant injury, as well as better define mechanisms through which these channels are regulated and mediate their effects. Therapeutic approaches to modulate activation of specific TRP channels are likely to have an important impact in reducing tissue damage in a number of diseases resulting from oxidant stress including ischemia/reperfusion injury and diabetes.