Ye M, Yang W, Ainscough J F, Hu X-P, Li X, Sedo A, Zhang X-H, Zhang X, Chen Z, Li X-M, Beech D J, Sivaprasadarao A, Luo J-H, Jiang L-H
Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
1] Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China [2] School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Cell Death Dis. 2014 Nov 27;5(11):e1541. doi: 10.1038/cddis.2014.494.
Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn(2+) level ([Zn(2+)]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn(2+)]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn(2+)]c but abolished the cytosolic Zn(2+) accumulation during reperfusion as well as ROS-elicited increases in the [Zn(2+)]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn(2+)]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury.
短暂性缺血是认知功能障碍的主要原因。缺血后活性氧（ROS）的产生以及胞质锌离子水平（[Zn(2+)]c）的升高在海马CA1区锥体神经元延迟性死亡中起关键作用，但其潜在机制尚未完全明确。在此，我们研究了对ROS敏感的瞬时受体电位M型2（TRPM2）通道的作用。利用体内和体外缺血再灌注模型，我们发现TRPM2基因敲除可强烈抑制[Zn(2+)]c的延迟性升高、ROS的产生、CA1区锥体神经元死亡以及缺血后记忆障碍。延时成像显示，TRPM2缺乏对缺血诱导的[Zn(2+)]c升高无影响，但可消除再灌注期间胞质锌离子的积累以及ROS引发的[Zn(2+)]c升高。这些结果首次证明了再灌注期间TRPM2通道激活在[Zn(2+)]c延迟性升高和CA1区锥体神经元死亡中起关键作用，并确定TRPM2是将ROS产生信号传导至缺血性脑损伤的关键分子。
