Identification YZ-001 As A Novel Inhibitor Of TRPM2 Channel

Background Transient receptor potential melastatin 2 (TRPM2) channel is an nonselective cation channel which widely spreads in the brain. As a cellular redox sensor which can be activated by ROS and metabolites of NAD+, it is involved in many physiological processes which relate to oxidative stress. Recent studies have shown that TRPM2 channel was involved in the process of cerebral stroke and played a significant role in inducing neuron cell death. Thus, specific inhibitors which can block TRPM2 channel may be a new therapeutic tool for treatment of cerebral stroke. Objectives To identify YZ-001 as a new inhibitors which can specifically block TRPM2 channel. Methods Using whole-cell recording to explore the influence of many newly synthesized YZ-001 on TRPM2 channel current; constructing mutants of TRPM2 by molecular biological methods to find the binding sites of YZ-001 on TRPM2 protein;Results Compound YZ-001 blocked TRPM2 channel currents in concentration dependent manner, the half inhibitory concentration of YZ-001 was 4.3 μM;single site mutations of extracellular pore region of TRPM2 channel affected the inhibition of YZ-001 in different ways, among them, E994A, H995A E1010A, E1022A residues were key positions; YZ-001 has little effect on the function of acid-sensing channel, voltage-dependent sodium channels, voltage-dependent potassium channel and NMDA receptor. Conclusion YZ-001 is a strong inhibitor of TRPM2 channels with relatively high specificity.