Physiological role of neuronal glutamate transporters: control of extrasynaptic glutamate diffusion-mediated modification of synaptic transmission

响应于攀爬纤维（CF）的重复激活，小脑皮质中篮状细胞（BC）-浦肯野细胞（PC）突触处的GABA释放通过CF递质谷氨酸的突触外扩散和随后表达在BC轴突终末上的AMPA受体的激活而被抑制。我们发现CF诱导的小脑GABA能传递的突触前抑制被临床相关浓度（25-50 mM）的乙醇（EtOH）抑制。阻断神经元谷氨酸转运体EAAT 4不仅能增强CF对GABA能传递的抑制作用，而且能消除EtOH对CF抑制作用的抑制作用。蛋白激酶C（PKC）和磷脂酰肌醇3-激酶（PI 3 K）的抑制剂可减弱EtOH的作用。这些结果表明，EtOH通过PKC/PI 3 K介导的蛋白磷酸化急剧增强PC中EAAT 4介导的谷氨酸摄取。

In response to repetitive activation of the climbing fibers (CFs), GABA release at basket cell (BC)-Purkinje cell (PC) synapses in the cerebellar cortex is suppressed through extrasynaptic diffusion of the CF transmitter glutamate and following activation of AMPA receptors that expressed on BC axon terminals. We found that the CF-induced presynaptic inhibition of cerebellar GABAergic transmission is suppressed by ethanol (EtOH) at a clinically relevant concentration (25-50 mM). Pharmacological blockade of the neuronal glutamate transporter EAAT4 not only augmented the CF-induced inhibition of GABAergic transmission but also abolished the suppressive action of EtOH on the CF-induced inhibition. This EtOH action was diminished by inhibitors for protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K). These results suggest that EtOH acutely potentiates EAAT4-mediated glutamate uptake in PCs through PKC/PI3K-mediated protein phosphorylation.