TY - JOUR T1 - Characterization and optimization of the novel TRPM2 antagonist tatM2NX JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.117549 SP - mol.119.117549 AU - I. Cruz-Torres AU - D.S. Backos AU - P.S. Herson Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/11/26/mol.119.117549.abstract N2 - TRPM2 is a calcium permeable channel activated by ADPR metabolites and oxidative stress. TRPM2 contributes to neuronal injury in the brain caused by stroke and cardiac arrest among other diseases including cancer, inflammation, and pain. However, the lack of specific inhibitors hinders the study of TRPM2 in brain pathophysiology. Here we present the design of a novel TRPM2 antagonist, tatM2NX, which prevents ligand binding and TRPM2 activation. We used mutagenesis of tatM2NX to determine the structure-activity relationship and antagonistic mechanism on TRPM2 using whole-cell patch clamp and Ca2+ imaging in HEK293 cells with stable human TRPM2 expression. We show that tatM2NX inhibits over 90% of TRPM2 channel currents at concentrations as low as 2μM. Moreover, tatM2NX is a potent antagonist with an IC50 of 396nM. Our results from tatM2NX mutagenesis indicate that specific residues within the tatM2NX C-terminus are required to confer antagonism on TRPM2. Therefore, the peptide tatM2NX represents a new tool for the study of TRPM2 function in cell biology and enhance our understanding of TRPM2 in disease.SIGNIFICANCE STATEMENT TatM2NX is a potent TRPM2 channel antagonist with the potential for clinical benefit in neurological diseases. This study characterizes interactions of tatM2NX with TRPM2 and the mechanism of action using structure-activity analysis. ER -