Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization
Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization
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DOI：
10.1038/emboj.2009.86
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发表时间：
2009-05-20
期刊：
影响因子：
11.4
通讯作者：
Mayer, Mark L.
中科院分区：
文献类型：
--
作者：
Chaudhry, Charu;Weston, Matthew C.;Mayer, Mark L.
AMPA 和红藻氨酸受体介导快速突触传递。 AMPA 受体配体结合域形成二聚体，是控制离子通道激活和脱敏的关键功能单元。二聚体稳定性与脱敏的速度和程度成反比。红藻氨酸和 AMPA 受体具有共同的结构元件，但功能测量表明这些亚型之间的亚基组装和门控有所不同。为了研究这一点，我们构建了 GluR6 红藻氨酸受体突变体文库，并通过分析超速离心直接测量红藻氨酸受体二聚体稳定性的变化，结合电生理实验，揭示了二聚体稳定性与脱敏率之间的负相关。我们解析了一系列五个 GluR6 突变体的晶体结构，以了解二聚体稳定的分子机制。我们证明红藻氨酸受体的脱敏状态作为一种深层能量很好地抵消了二聚体界面突变体的稳定作用，并且红藻氨酸受体反应的失活主要是进入脱敏状态。我们的结果表明，具有相似结构和门控机制的神经递质受体如何表现出截然不同的功能特性。 EMBO 杂志 (2009) 28, 1518-1530。 doi：10.1038/emboj.2009.86； 2009 年 4 月 2 日在线发布
AMPA and kainate receptors mediate fast synaptic transmission. AMPA receptor ligand-binding domains form dimers, which are key functional units controlling ion-channel activation and desensitization. Dimer stability is inversely related to the rate and extent of desensitization. Kainate and AMPA receptors share common structural elements, but functional measurements suggest that subunit assembly and gating differs between these subtypes. To investigate this, we constructed a library of GluR6 kainate receptor mutants and directly measured changes in kainate receptor dimer stability by analytical ultracentrifugation, which, combined with electrophysiological experiments, revealed an inverse correlation between dimer stability and the rate of desensitization. We solved crystal structures for a series of five GluR6 mutants, to understand the molecular mechanisms for dimer stabilization. We demonstrate that the desensitized state of kainate receptors acts as a deep energy well offsetting the stabilizing effects of dimer interface mutants, and that the deactivation of kainate receptor responses is dominated by entry into desensitized states. Our results show how neurotransmitter receptors with similar structures and gating mechanisms can exhibit strikingly different functional properties. The EMBO Journal (2009) 28, 1518-1530. doi:10.1038/emboj.2009.86; Published online 2 April 2009