Mechanism of modulation of AMPA receptors by TARP-γ8
Mechanism of modulation of AMPA receptors by TARP-γ8
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DOI：
10.1085/jgp.201912451
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发表时间：
2020-01-01
影响因子：
3.8
通讯作者：
Jayaraman, Vasanthi
中科院分区：
文献类型：
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作者：
Carrillo, Elisa;Shaikh, Sana A.;Jayaraman, Vasanthi
哺乳动物中枢神经系统的快速兴奋性突触传递是由谷氨酸激活的α -氨基5-甲基-3-羟基-4-异恶唑丙酸（AMPA）受体介导的。在神经元中，AMPA受体与跨膜AMPA受体调节蛋白（TARPs）共同聚集。与TARP γ - 8的组装改变了受体的生物物理特性，在谷氨酸持续存在的情况下产生重敏电流。通过单通道记录，我们发现在重敏条件下，GluA2 AMPA受体主要过渡到更高的电导水平，类似于环噻嗪存在时受体的激活，从而稳定了开放状态。为了研究与这些状态相关的构象，我们使用了单分子FRET，并表明这种高电导状态在受体的细胞外部分的亚基之间表现出更紧密的耦合。此外，从紧密耦合状态过渡到解耦状态的停留时间与通道打开时间的延长相关，从而在单分子水平上关联构象和功能。
Fast excitatory synaptic transmission in the mammalian central nervous system is mediated by glutamate-activated alpha-amino5-methyl-3-hydroxy-4-isoxazole propionate (AMPA) receptors. In neurons, AMPA receptors coassemble with transmembrane AMPA receptor regulatory proteins (TARPs). Assembly with TARP gamma 8 alters the biophysical properties of the receptor, producing resensitization currents in the continued presence of glutamate. Using single-channel recordings, we show that under resensitizing conditions, GluA2 AMPA receptors primarily transition to higher conductance levels, similar to activation of the receptors in the presence of cyclothiazide, which stabilizes the open state. To study the conformation associated with these states, we have used single-molecule FRET and show that this high-conductance state exhibits tighter coupling between subunits in the extracellular parts of the receptor. Furthermore, the dwell times for the transition from the tightly coupled state to the decoupled states correlate to longer open durations of the channels, thus correlating conformation and function at the single-molecule level.