The Inhibitory Effect of α/β-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors.
The Inhibitory Effect of α/β-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors.
复制标题
含有 α/β-水解酶结构域 6 (ABHD6) 对含有 GluA2 和 GluA3 的 AMPA 受体表面靶向的抑制作用。
DOI：
10.3389/fnmol.2017.00055
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发表时间：
2017
影响因子：
4.8
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Wei M;Jia M;Zhang J;Yu L;Zhao Y;Chen Y;Ma Y;Zhang W;Shi YS;Zhang C
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体（AMPARs）是哺乳动物大脑中介导快速神经传递的主要兴奋性受体。功能性AMPARs的表面表达对突触的传递和可塑性至关重要。AMPAR辅助亚基控制AMPAR的生物合成、膜运输和突触靶向。我们之前的研究表明，AMPARs的一个辅助亚基- α/β-水解酶结构域6 （ABHD6）在异源细胞和神经元中抑制含glua1受体的膜传递和功能。然而，ABHD6是否影响谷氨酸受体亚单位GluA2和GluA3的膜运输尚不清楚。在这里，我们研究了ABHD6在表达GluA1、GluA2、GluA3和stargazin的HEK293T细胞中过表达的影响，无论是单独表达还是联合表达。结果表明，在HEK293T细胞中，当表达GluA2或GluA3时，ABHD6抑制谷氨酸诱导电流和AMPARs的膜表达。我们构建了一系列GluA2和GluA3的c端缺失构建体，并证实了ABHD6对谷氨酸诱导电流和GluAs表面表达的抑制作用需要GluAs的c端。同时，我们的下拉实验表明，ABHD6与GluA1-3结合，而GluAs的c端结构域的缺失使这种结合消失。这些发现表明，ABHD6抑制AMPAR介导的电流及其表面表达，与AMPAR亚基的类型无关，该抑制剂的作用是通过与GluAs c -末端区域的结合介导的。
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are major excitatory receptors that mediate fast neurotransmission in the mammalian brain. The surface expression of functional AMPARs is crucial for synaptic transmission and plasticity. AMPAR auxiliary subunits control the biosynthesis, membrane trafficking, and synaptic targeting of AMPARs. Our previous report showed that α/β-hydrolase domain-containing 6 (ABHD6), an auxiliary subunit for AMPARs, suppresses the membrane delivery and function of GluA1-containing receptors in both heterologous cells and neurons. However, it remained unclear whether ABHD6 affects the membrane trafficking of glutamate receptor subunits, GluA2 and GluA3. Here, we examine the effects of ABHD6 overexpression in HEK293T cells expressing GluA1, GluA2, GluA3, and stargazin, either alone or in combination. The results show that ABHD6 suppresses the glutamate-induced currents and the membrane expression of AMPARs when expressing GluA2 or GluA3 in the HEK293T cells. We generated a series of GluA2 and GluA3 C-terminal deletion constructs and confirm that the C-terminus of GluAs is required for ABHD6’s inhibitory effects on glutamate-induced currents and surface expression of GluAs. Meanwhile, our pull-down experiments reveal that ABHD6 binds to GluA1–3, and deletion of the C-terminal domain of GluAs abolishes this binding. These findings demonstrate that ABHD6 inhibits the AMPAR-mediated currents and its surface expression, independent of the type of AMPAR subunits, and this inhibitor’s effects are mediated through the binding with the GluAs C-terminal regions.