A critical role of TRPM2-NMDAR coupling in excitotoxicity during ischemic stroke.
Ischemic stroke is a major cause of death worldwide. To develop better therapies, Dr. Yue’s group focuses on investigating the mechanisms of ischemic neuronal death, which is classically thought to be induced by N-Methyl-D-aspartate receptors (NMDAR)-mediated excitotoxicity during ischemic stroke. However, all NMDAR antagonists failed to alleviate ischemic stroke in clinical trials. TRPM2 is a heat-sensitive and calcium-permeable ion channel that is usually activated by inflammatory conditions, and inflammation is also a prominent feature of ischemic stroke. Global TRPM2 knockout has long been found to protect mice against ischemic stroke, but the underlying cellular and molecular mechanisms remain elusive.
Recently, Pengyu Zong, a graduate student in Yue lab, discovered that TRPM2 plays a critical role in the NMDAR-mediated ischemic excitotoxicity by physically and functionally coupling with NMDAR. Neuronal TRPM2 deletion reduces ischemic brain injury and prevent the compromise of cognitive functions after ischemic stroke in mice. Importantly, an interfering peptide selectively dissociating the binding between TRPM2 and NDMAR effectively attenuates ischemic stroke in mice. Taken together, their studies reveal an important mechanism for understanding ischemic excitotoxicity and generate a novel therapeutic strategy for ischemic stroke. Moreover, excitotoxicity is also an important cause of many other neurological diseases including Alzheimer’s disease, suggesting that TRPM2-NDMAR uncoupling may also be a promising therapeutic strategy for other NMDAR-related diseases.
Pengyu’s work has recently been published in Neuron. The press release was published in UConn Today. Pengyu also won a travel award from American Heart Association for attending the Basic Cardiovascular Science meeting held from 07/24-07/28 at Chicago, IL (featured here). Pengyu’s poster was rated among the tops and was chosen for presentation at the Best of Specialty Conferences during the biggest annual meeting of American Heart Association at Chicago in this November.