LTRPC2 Ca²⁺-Permeable channel activated by changes in redox status confers susceptibility to cell death

Redox status changes exert critical impacts on necrotic/apoptotic and normal cellular processes. We report here a widely expressed Ca²⁺-permeable cation channel, LTRPC2, activated by micromolar levels of H₂O₂ and agents that produce reactive oxygen/nitrogen species. This sensitivity of LTRPC2 to redox state modifiers was attributable to an agonistic binding of nicotinamide adenine dinucleotide (β-NAD⁺) to the MutT motif. Arachidonic acid and Ca²⁺ were important positive regulators for LTRPC2. Heterologous LTRPC2 expression conferred susceptibility to death on HEK cells. Antisense oligonucleotide experiments revealed physiological involvement of "native" LTRPC2 in H₂O₂- and TNFα-induced Ca²⁺ influx and cell death. Thus, LTRPC2 represents an important intrinsic mechanism that mediates Ca²⁺ and Na⁺ overload in response to disturbance of redox state in cell death.