The role of GABAAR phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition.
The role of GABAAR phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition.
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DOI：
10.1042/bst0371355
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发表时间：
2009-12
影响因子：
3.9
通讯作者：
Moss SJ
中科院分区：
文献类型：
--
作者：
Vithlani M;Moss SJ
γ-氨基丁酸A型受体（GABAAR）是异五聚体氯离子选择性配体门控离子通道，其介导脑中的快速抑制，并且是苯二氮卓类、巴比妥类、神经类固醇和全身麻醉剂的关键治疗靶标。在脑中，大多数苯二氮卓类敏感性突触受体亚型由α1-3、β1-3和γ2亚基组装而成。虽然很明显，GABAAR功能的药理学操作可以对行为产生深远的影响，但神经元用于促进神经元抑制功效持续变化的内源性机制仍有待记录。越来越清楚的是，GABAARs经历显著的组成性内吞速率，并调节可决定突触抑制功效的再循环过程。它们的内吞作用通过受体β1-3和γ2亚基的细胞内结构域内的特异性内吞作用基序与网格蛋白衔接蛋白AP 2的直接结合来调节。这些结合基序包含GABAAR内丝氨酸和酪氨酸磷酸化的主要位点。它们的磷酸化可以对与AP 2的结合产生显著影响。在这篇综述中，我们评估的作用，这些磷酸依赖的相互作用发挥调节抑制性突触的建设，神经元抑制和神经元结构的功效。
γ-aminobutyric acid type-A receptors (GABAARs) are heteropentameric chloride-selective ligand-gated ion channels that mediate fast inhibition in the brain and are key therapeutic targets for benzodiazepines, barbiturates, neurosteroids and general anesthetics. In the brain the majority of benzodiazepine-sensitive synaptic receptor subtypes are assembled from α1–3, β1–3 and γ2 subunits. Whilst it is evident that the pharmacological manipulation of GABAAR function can have profound effects on behavior, the endogenous mechanisms that neurons use to promote sustained changes in the efficacy of neuronal inhibition remain to be documented. It is increasingly clear that GABAARs undergo significant rates of constitutive endocytosis and regulate recycling processes that can determine efficacy of synaptic inhibition. Their endocytosis is regulated via the direct binding of specific endocytosis motifs within the intracellular domains of receptor β1–3 and γ2 subunits to the clathrin adaptor protein AP2. These binding motifs contain major sites of both serine and tyrosine phosphorylation within GABAARs. Their phosphorylation can have dramatic effects on binding to AP2. In this review we evaluate the role that these phospho-dependent interactions play in regulating the construction of inhibitory synapses, the efficacy of neuronal inhibition and neuronal structure.