Astrocytic control of synaptic NMDA receptors
Astrocytic control of synaptic NMDA receptors
复制标题
DOI：
10.1113/jphysiol.2007.130377
复制
发表时间：
2007-06-15
影响因子：
5.5
通讯作者：
Traynelis, Stephen F.
中科院分区：
文献类型：
--
作者：
Lee, C. Justin;Mannaioni, Guido;Traynelis, Stephen F.
星形胶质细胞表达多种G蛋白偶联受体，可触发细胞内Ca 2+的释放，包括P2 Y、缓激肽和蛋白酶激活受体（PARs）。通过使用高度敏感的嗅探器补丁技术，我们证明，激活P2Y受体，缓激肽受体和蛋白酶激活受体都刺激谷氨酸释放培养或急性分离的星形胶质细胞。在这些受体中，我们利用PAR 1作为模型系统，因为其具有良好的药理学和分子工具，在星形胶质细胞中的显著表达及其与神经病理过程的高度相关性。体外星形胶质细胞PAR 1介导的谷氨酸释放是Ca 2+依赖性的，并激活培养物中邻近神经元上的NMDA受体。海马切片中星形胶质细胞PAR 1的激活诱导CA1神经元中的APV敏感性内向电流，并导致CA1神经元中的APV敏感性神经元去极化，与星形胶质细胞释放谷氨酸一致。PAR 1激活以Mg 2+依赖的方式增强NMDA受体介导的突触微型EPSC、诱发的EPSC和诱发的EPSP的成分，这可能反映了在随后的突触电流期间脊头部去极化和随后的NMDA受体Mg 2+阻断的减少。PAR 1激活后星形胶质细胞释放谷氨酸也可能导致谷氨酸占据一些突触周NMDA受体，这些受体在突触去极化期间缓解紧张性Mg 2+阻滞后传递电流。这些结果表明，星形胶质细胞G蛋白偶联受体，增加细胞内Ca 2+可以调节突触NMDA受体的反应。
Astrocytes express a wide range of G-protein coupled receptors that trigger release of intracellular Ca2+, including P2Y, bradykinin and protease activated receptors (PARs). By using the highly sensitive sniffer-patch technique, we demonstrate that the activation of P2Y receptors, bradykinin receptors and protease activated receptors all stimulate glutamate release from cultured or acutely dissociated astrocytes. Of these receptors, we have utilized PAR1 as a model system because of favourable pharmacological and molecular tools, its prominent expression in astrocytes and its high relevance to neuropathological processes. Astrocytic PAR1-mediated glutamate release in vitro is Ca2+ dependent and activates NMDA receptors on adjacent neurones in culture. Activation of astrocytic PAR1 in hippocampal slices induces an APV-sensitive inward current in CA1 neurones and causes APV-sensitive neuronal depolarization in CA1 neurones, consistent with release of glutamate from astrocytes. PAR1 activation enhances the NMDA receptor-mediated component of synaptic miniature EPSCs, evoked EPSCs and evoked EPSPs in a Mg2+-dependent manner, which may reflect spine head depolarization and consequent reduction of NMDA receptor Mg2+ block during subsequent synaptic currents. The release of glutamate from astrocytes following PAR1 activation may also lead to glutamate occupancy of some perisynaptic NMDA receptors, which pass current following relief of tonic Mg2+ block during synaptic depolarization. These results suggest that astrocytic G-protein coupled receptors that increase intracellular Ca2+ can tune synaptic NMDA receptor responses.