Abstract
Receptor stimulation and other cellular stimulations such as heat, osmotic stress and oxidative stress evoke activation of Ca^<2+> -permeable cation channels. Recent studies have demonstrated that molecular entities of these Ca^<2+> -permeable cation channels are formed by mammalian homologues of Drosophila transient receptor potential (TRP) proteins. We have identified that a widely expressed Ca^<2+> -permeable cation channel TRPM2 is activated by reactive oxygen or nitrogen species-generating agents including H_2O_2 of micromolar levels. This sensitivity of TRPM2 to redox state modifiers was attributable to an agonistic binding of nicotinamide adenine dinucleotide (β-NAD^+) to the MutT, a nucleotide binding motif. In native and heterologous expression system, TRPM2 was involved in H_2O_2 - induced Ca^<2+> influx and cell death. Thus, TRPM2 represents an important intrinsic mechanism that mediates Ca^<2+> and Na^+ overload in response to disturbance of redox state in cell death.
