To test the hypothesis that adenosine diphosphoribose (ADPR) acts as a second messenger we performed experiments in Jurkat T cells. We now show that stimulation of these cells by high concentrations of concanavalin A (ConA) induced an elevation of the ADPR concentration and activated an inward current different from the Ca2+ release-activated Ca2+ current (ICRAC). The electrophysiological properties of this current suggested that it was mediated by TRPM2. Infusion of ADPR using the whole-cell mode of the patch-clamp technique activated a current with similar properties. RT-PCR demonstrated that Jurkat cells express TRPM2 channel subunits. In addition, Western blot analysis showed the presence of TRPM2 protein in the plasma membrane of Jurkat T cells. Confocal microscopy showed that TRPM2 is localized mainly in the cell surface. Inhibition of ADPR formation with the NADase inhibitor 3GA reduced the ConA-mediated, but not the store-operated Ca2+ entry and prevented the ConA-induced cell death of Jurkat cells. Moreover, gene silencing of TRPM2 abolished the ADPR- and ConA-mediated inward current. Thus, ADPR is a novel second messenger significantly involved in ConA-mediated cell death in T cells.