TREK-1 and Best1 Channels Mediate Fast and Slow Glutamate Release in Astrocytes upon GPCR Activation
TREK-1 and Best1 Channels Mediate Fast and Slow Glutamate Release in Astrocytes upon GPCR Activation
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DOI：
10.1016/j.cell.2012.09.005
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发表时间：
2012-09-28
期刊：
影响因子：
64.5
通讯作者：
Lee, C. Justin
中科院分区：
文献类型：
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作者：
Woo, Dong Ho;Han, Kyung-Seok;Lee, C. Justin
星形胶质细胞在激活各种 GPCR 后释放谷氨酸，在突触功能中发挥重要作用。然而，释放的分子机制一直存在争议。在这里，我们报告了两种动力学上不同的非囊泡、通道介导的谷氨酸释放模式。快速模式需要激活 G(alpha i)、解离 G(beta gamma)，然后通过 G(beta gamma) 和 TREK-1 N 末端之间的直接相互作用打开谷氨酸可渗透的双孔结构域钾通道 TREK-1。慢速模式是 Ca2+ 依赖性的，需要 G(alpha q) 激活并打开谷氨酸可渗透的、Ca2+ 激活的阴离子通道 Best1。超微结构分析表明，TREK-1 优先定位于细胞体和突起，而 Best1 主要存在于突触附近的星形胶质细胞的微区中。扩散模型预测，快速模式可以靶向神经元 mGluR，谷氨酸峰值浓度为 100 μM，而慢速模式可以靶向神经元 NMDA 受体，浓度约为 1 μM。我们的结果揭示了星形胶质细胞谷氨酸的两种不同来源，它们可以对邻近神经元产生不同的影响。
Astrocytes release glutamate upon activation of various GPCRs to exert important roles in synaptic functions. However, the molecular mechanism of release has been controversial. Here, we report two kinetically distinct modes of nonvesicular, channel-mediated glutamate release. The fast mode requires activation of G(alpha i), dissociation of G(beta gamma), and subsequent opening of glutamate-permeable, two-pore domain potassium channel TREK-1 through direct interaction between G(beta gamma) and N terminus of TREK-1. The slow mode is Ca2+ dependent and requires G(alpha q) activation and opening of glutamate-permeable, Ca2+-activated anion channel Best1. Ultrastructural analyses demonstrate that TREK-1 is preferentially localized at cell body and processes, whereas Best1 is mostly found in microdomains of astrocytes near synapses. Diffusion modeling predicts that the fast mode can target neuronal mGluR with peak glutamate concentration of 100 mu M, whereas slow mode targets neuronal NMDA receptors at around 1 mu M. Our results reveal two distinct sources of astrocytic glutamate that can differentially influence neighboring neurons.