![]() At physiologic membrane potentials, activation of TRPM2 results in influx of sodium and calcium (Ca2+) into the cell. The transient receptor potential melastatin 2 (TRPM2) is a nonselective cation channel from the TRP family. Therefore, the peptide tatM2NX represents a new tool for the study of TRPM2 function in cell biology and enhances our understanding of TRPM2 in disease. Our results from tatM2NX mutagenesis indicate that specific residues within the tatM2NX C terminus are required to confer antagonism on TRPM2. Moreover, tatM2NX is a potent antagonist with an IC 50 of 396 nM. We show that tatM2NX inhibits over 90% of TRPM2 channel currents at concentrations as low as 2 μM. We used mutagenesis of tatM2NX to determine the structure–activity relationship and antagonistic mechanism on TRPM2 using whole-cell patch clamp and Calcium imaging in human embryonic kidney 293 cells with stable human TRPM2 expression. ![]() Here, we present the design of a novel TRPM2 antagonist, tatM2NX, which prevents ligand binding and TRPM2 activation. However, the lack of specific inhibitors hinders the study of TRPM2 in brain pathophysiology. TRPM2 contributes to neuronal injury in the brain caused by stroke and cardiac arrest among other diseases including pain, inflammation, and cancer. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable channel activated by adenosine diphosphate ribose metabolites and oxidative stress.
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