TRPM2通道在缺血引发的延迟性神经元死亡中的机制研究

发布时间：2018-05-11 16:53

本文选题：TRPM2 + 锌离子　；参考：《浙江大学》2014年博士论文

【摘要】：TRPM2(Transient Receptor Potential cation channel, subfamily M, member2)是一类非选择性阳离子通道,在神经系统中有广泛表达。近期的研究表明TRPM2通道有参与到神经元死亡过程中。但是,对于TRPM2在缺血中的作用还知之甚少。在本研究中,我们发现了在缺血再灌时TRPM2可以通过锌离子,并介导了神经元的延迟性死亡。首先,我们明确TRPM2通道在海马CA1区的锥体细胞有较高水平的表达。同时,我们还发现TRPM2的独特激活方式,只有NMDA刺激和电极内液中加ADPR同时作用,才能记录到海马CA1锥体细胞的TRPM2电流；而在TRPM2功能缺失的神经元上,记录不到TRPM2的电流。TRPM2全身性功能性缺失不会影响小鼠脑的基本发育和运动能力。由于C57小鼠脑基地的Willis环天生发育不完整,可以使用双侧颈总动脉结扎的方法模拟全脑短暂缺血。我们发现TRPM2通道参与缺血引起的海马神经元死亡过程。TPRM2功能缺失的小鼠在缺血以后,不但在存活的神经元数量多于同样缺血的野生型小鼠,而且在行为学测试上优于野生型小鼠。此外,我们还进一步的对TRPM2口何参与神经元死亡中进行了深入了研究。首先,我们发现,在异源TRPM2表达系统中,TRPM2的激活,可以观察到胞内的锌离子增高。并且,神经元中的TRPM2可以介导胞内锌离子增高,通透锌离子。TRPM2功能性缺失后大大降低了缺血引起的海马CA1区神经元胞内的锌离子堆积。接着,我们发现TRPM2主要参与了再灌阶段的锌离子增高,而对缺血过程中锌离子没有影响。综上所述,在本研究中我们采用电生理和组织染色方法和使用全脑缺血模型,阐明TRPM2通道在缺血再灌阶段引起了胞内锌离子增高,进而导致神经元死亡。这对于阐明缺血过程中神经元死亡的机制具有重要的意义。
[Abstract]:TRPM2(Transient Receptor Potential cation channel, subfamily M, member2) is a class of nonselective cation channels, which is widely expressed in the nervous system. Recent studies have shown that TRPM2 channels are involved in neuronal death. However, little is known about the role of TRPM2 in ischemia. In this study, we found that TRPM2 mediated delayed neuronal death through zinc ions during ischemia and reperfusion. First of all, we confirm that the TRPM2 channel has high expression in the pyramidal cells of the hippocampal CA1 region. At the same time, we also found that the unique activation mode of TRPM2 was that the TRPM2 current in the hippocampal CA1 pyramidal cells could be recorded only by NMDA stimulation and the addition of ADPR in the electrode fluid, while in the neurons with the missing TRPM2 function, the TRPM2 current in the hippocampal CA1 pyramidal cells could be recorded. The absence of TRPM2 current. TRPM2 functional deficiency did not affect the basic development and motor ability of mouse brain. Because the Willis ring in the brain base of C57 mice is incompletely developed, bilateral common carotid artery ligation can be used to simulate transient global ischemia. We found that TRPM2 channel involved in the process of hippocampal neuronal death induced by ischemia. After ischemia, the number of surviving neurons in mice with loss of function of TPRM2 was more than that of wild-type mice with the same ischemia. And the behavior test is superior to that of wild mice. In addition, we further studied how TRPM2 is involved in neuronal death. First, we found that the activation of TRPM2 in the heterologous TRPM2 expression system showed that the increase of zinc ions in the cell was observed. Moreover, TRPM2 in neurons can mediate the increase of intracellular zinc ions, which can significantly reduce the accumulation of zinc ions in neurons of hippocampal CA1 region induced by ischemia after the functional deletion of zinc ions. Then, we found that TRPM2 was mainly involved in the increase of zinc ion during reperfusion, but had no effect on zinc ion during ischemia. In conclusion, we used electrophysiological and tissue staining methods and global cerebral ischemia model to elucidate that TRPM2 channel induced the increase of intracellular zinc ion during ischemia and reperfusion, which resulted in neuronal death. It is important to elucidate the mechanism of neuronal death during ischemia.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R741

【共引文献】