2-Propenamide, 2-cyano-3-(3,5-dichlorophenyl)-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-

TPC2-A1-N is a powerful and Ca2+-permeable agonist oftwo porechannel2(TPC2), which plays its role by mimicking the physiological actionsofNAADP. TPC2-A1-P reproduciblyevokes significant Ca2+ responses from TPC2 (EC50=7.8 μM), and the effect can be blocked by several TPC blockers. TPC2-A1-N can be used to probe different functions of TPC2 channels in intact cells[1][2].

TPC2-A1-N is a selective two pore segment channel 2 (TCP2) agonist th at mimics the action of NAADP where it selectively induces fast Ca2+ signals (EC50 = 7.8 μM) in a TCP2-dependent manner, without potency toward TRPML1/2/3. In contrast, TPC2-A1-N is a much weaker Na+ current inducer when compared to PI(3,5)P2 and TPC2-A1-P. TPC2-A1-N, but not the Na+ signals agonist TPC2-A1-P causes TPC2-dependent alkalinization of lysosomal lumen Ca2+ stores (10 μM, TPC2-expressing HeLa cells), while TPC2-A1-P, but not TPC2-A1-N, activates TPC2-dependent lysosomal exocytosis (30 μM, murine macrophages).

[1] Susanne Gerndt, et al. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife DOI:10.7554/eLife.54712
[2] Xuhui Jin, et al. Targeting Two-Pore Channels: Current Progress and Future Challenges. Trends Pharmacol Sci. 2020 Aug;41(8):582-594. DOI:10.1016/j.tips.2020.06.002