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TRPM2 (previously designated TRPC7 or LTRPC2) is a Ca2+-permeable nonselective cation channel that contains a C-terminal enzymatic domain with pyrophosphatase activity, which specifically binds ADP-ribose. Cyclic ADP-ribose (cADPR) and hydrogen peroxide (H2O2) can facilitate ADPR-mediated activation of heterologously expressed TRPM2. Here, we show that the two Ca2+-mobilizing second messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) strongly activate natively expressed TRPM2 channels in Jurkat T cells. TRPM2 activation by both agonists can be partially suppressed by the ADPR antagonist adenosine monophosphate (AMP), which suggests that cADPR and NAADP lead to mobilization of endogenous ADPR presumably via metabolic conversion. The remaining channel activity is due to direct gating of TRPM2 by the two agonists and can be completely suppressed by 8-Br-cADPR, which suggests that cADPR and NAADP share a common binding site on TRPM2 that can regulate TRPM2 activity in synergy with ADPR. We conclude that cADPR and NAADP, in combination with ADPR, represent physiological co-activators of TRPM2 that contribute to Ca2+ influx in T lymphocytes and presumably other cell types that express this channel.