Dynamic regulation of the Kv2.1 voltage-gated potassium channel during brain ischemia through neuroglial interaction.
Dynamic regulation of the Kv2.1 voltage-gated potassium channel during brain ischemia through neuroglial interaction.
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DOI：
10.1523/jneurosci.1417-08.2008
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发表时间：
2008-08-20
期刊：
影响因子：
--
通讯作者：
Cai X
中科院分区：
文献类型：
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作者：
Misonou H;Thompson SM;Cai X
中枢神经系统中神经胶质细胞相互作用的生理意义在癫痫和脑缺血等神经系统疾病中得到强调。Kv2.1电压门控钾通道的独特之处在于它能够在神经元细胞体的质膜上形成大簇。我们之前已经证明，脑缺血会导致Kv2.1亚基的快速去磷酸化，并导致离子通道功能的激活。然而，通道聚集的生理意义尚不清楚。在这里，我们提出的证据表明，神经元质膜上聚集的Kv2.1通道与轴体突触并列，并与表达高水平谷氨酸转运体的星形细胞突起有关。在急性皮质脑片中，缺血应激迅速导致Kv2.1的去磷酸化和弥散。选择性抑制星形胶质细胞的代谢足以诱导神经元的Kv2.1去磷酸化。有趣的是，这些效应被离子型谷氨酸受体的拮抗剂阻断，表明谷氨酸作为星形胶质细胞和神经元之间的信号媒介参与其中。此外，药物抑制胶质细胞谷氨酸转运体GLT-1可引起类似的Kv2.1去磷酸化，而外源性谷氨酸单独作用不明显。这些结果表明，缺血应激迅速导致星形胶质细胞谷氨酸转运体功能障碍，并导致谷氨酸在细胞外空间积聚。升高的谷氨酸可能随后激活离子型谷氨酸受体，导致神经元中Kv2.1的去磷酸化。这些发现表明，Kv2.1簇位于神经胶质细胞连接处，通过谷氨酸信号实现对缺血应激的快速调制。
The physiological significance of neuroglial interactions in the central nervous system has been emphasized in neurological conditions such as epilepsy and brain ischemia. The Kv2.1 voltage-gated potassium channel is unique in its ability to form large clusters in the plasma membrane of neuronal cell bodies. We have previously shown brain ischemia causes rapid dephosphorylation of Kv2.1 subunits and resultant activation of the ion channel function. However, the physiological significance of the channel clustering is unknown. Here we present evidence that clustered Kv2.1 channels in the neuronal plasma membrane are juxtaposed to axosomatic synapses and associated with astrocytic processes expressing high levels of glutamate transporters. In acute cortical slices, ischemic stress rapidly resulted in the dephosphorylation and dispersion of Kv2.1. Selective inhibition of metabolism in astrocytes was sufficient to induce Kv2.1 dephosphorylaion in neurons. Interestingly, these effects were blocked by the antagonists of ionotropic glutamate receptors, indicating the involvement of glutamate as the signal mediator between astrocytes and neurons. Furthermore, the pharmacological inhibition of glial glutamate transporter GLT-1 induced the similar Kv2.1 dephosphorylation, whereas exogeneous glutamate alone was not efficacious. These results suggest that ischemic stress rapidly causes the dysfunction of glutamate transporters in astrocytes and resultant accumulation of glutamate in the extracellular space. The elevated glutamate may subsequently activate ionotropic glutamate receptors and result in the dephosphorylation of Kv2.1 in neurons. These findings implicate that Kv2.1 clusters are strategically situated at neuroglial junctions to achieve the rapid modulation upon ischemic stress via glutamate signaling.