Molecular Mechanism of AMPA Receptor Modulation by TARP/Stargazin
Molecular Mechanism of AMPA Receptor Modulation by TARP/Stargazin
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DOI：
10.1016/j.neuron.2017.01.032
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发表时间：
2017-03-08
期刊：
影响因子：
16.2
通讯作者：
Stern-Bach, Yael
中科院分区：
文献类型：
--
作者：
Ben-Yaacov, Anat;Gillor, Moshe;Stern-Bach, Yael
AMPA受体（AMPAR）介导大脑中大部分快速兴奋性传递，并对突触可塑性和病理学有重要贡献。AMPAR的运输和门控由辅助跨膜AMPAR调节蛋白（TARP）严格控制。在这里，使用系统的结构域交换与TARP不敏感的红藻氨酸受体GluK 2，我们表明，AMPAR与原型TARP stargazin/g2的相互作用主要涉及AMPAR膜结构域M1和M4的相邻亚基，启动或稳定的AMPAR C-尾，这些相互作用足以使充分的受体调节。此外，采用TARP嵌合体还公开了TARP跨膜结构域TM 3和TM 4以及细胞外环2在该过程中的关键作用。从机制上讲，我们的数据支持两步作用，其中TARP与AMPAR膜结构域的结合使通道关闭状态不稳定，从而在激动剂结合时实现有效的开放，然后通过随后的相互作用稳定开放状态。
AMPA receptors (AMPARs) mediate the majority of fast excitatory transmission in the brain and critically contribute to synaptic plasticity and pathology. AMPAR trafficking and gating are tightly controlled by auxiliary transmembrane AMPAR regulatory proteins (TARPs). Here, using systematic domain swaps with the TARP-insensitive kainate receptor GluK2, we show that AMPAR interaction with the prototypical TARP stargazin/g2 primarily involves the AMPAR membrane domains M1 and M4 of neighboring subunits, initiated or stabilized by the AMPAR C-tail, and that these interactions are sufficient to enable full receptor modulation. Moreover, employing TARP chimeras disclosed a key role in this process also for the TARP transmembrane domains TM3 and TM4 and extracellular loop 2. Mechanistically, our data support a two-step action in which binding of TARP to the AMPAR membrane domains destabilizes the channel closed state, thereby enabling an efficient opening upon agonist binding, which then stabilizes the open state via subsequent interactions.