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首页> 美国卫生研究院文献>The Journal of Neuroscience >Neuronal Gap Junction Coupling Is Regulated by Glutamate and Plays Critical Role in Cell Death during Neuronal Injury
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Neuronal Gap Junction Coupling Is Regulated by Glutamate and Plays Critical Role in Cell Death during Neuronal Injury

机译：神经元间隙连接耦合受谷氨酸调节并在神经元损伤期间在细胞死亡中起关键作用。

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In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI), and epilepsy. The coupling of neurons by gap junctions (electrical synapses) increases during neuronal injury. We report here that the ischemic increase in neuronal gap junction coupling is regulated by glutamate via group II metabotropic glutamate receptors (mGluRs). Specifically, using electrotonic coupling, Western blots, and siRNA in the mouse somatosensory cortex in vivo and in vitro, we demonstrate that activation of group II mGluRs increases background levels of neuronal gap junction coupling and expression of connexin 36 (Cx36) (neuronal gap junction protein), and inactivation of group II mGluRs prevents the ischemia-mediated increases in the coupling and Cx36 expression. We also show that the regulation is via cAMP/PKA (cAMP-dependent protein kinase)-dependent signaling and posttranscriptional control of Cx36 expression and that other glutamate receptors are not involved in these regulatory mechanisms. Furthermore, using the analysis of neuronal death, we show that inactivation of group II mGluRs or genetic elimination of Cx36 both dramatically reduce ischemia-mediated neuronal death in vitro and in vivo. Similar results are obtained using in vitro models of TBI and epilepsy. Our results indicate that neuronal gap junction coupling is a critical component of glutamate-dependent neuronal death. They also suggest that causal link among group II mGluR function, neuronal gap junction coupling, and neuronal death has a universal character and operates in different types of neuronal injuries.
机译：在哺乳动物的中枢神经系统中，谷氨酸的过度释放和谷氨酸受体的过度活化是造成神经元损伤（包括局部缺血，脑外伤（TBI）和癫痫）继发的（延迟的）神经元死亡的原因。在神经元损伤期间，神经元通过间隙连接（电突触）的耦合增加。我们在这里报告神经元间隙连接偶联的缺血性增加是由谷氨酸通过II组代谢型谷氨酸受体（mGluRs）调节的。具体而言，在体内和体外在小鼠体感皮层中使用电声耦合，蛋白质印迹和siRNA，我们证明了II组mGluRs的激活增加了神经元间隙连接偶联的背景水平和连接蛋白36（Cx36）（神经间隙连接）的表达蛋白）和II组mGluR的失活可防止缺血介导的偶联和Cx36表达增加。我们还显示该调节是通过cAMP / PKA（cAMP依赖性蛋白激酶）依赖性信号传导和Cx36表达的转录后控制，而其他谷氨酸受体不参与这些调节机制。此外，使用神经元死亡的分析，我们表明，灭活II组mGluRs或遗传消除Cx36均可显着减少体外和体内缺血介导的神经元死亡。使用TBI和癫痫的体外模型可获得相似的结果。我们的结果表明，神经元间隙连接偶联是谷氨酸依赖性神经元死亡的重要组成部分。他们还表明，II组mGluR功能，神经元间隙连接偶联和神经元死亡之间的因果联系具有普遍性，并在不同类型的神经元损伤中起作用。

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