The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function
The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function
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DOI：
10.1042/bst0320529
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发表时间：
2004-06-01
影响因子：
3.9
通讯作者：
Wafford, KA
中科院分区：
文献类型：
--
作者：
Connolly, CN;Wafford, KA
Cys环受体构成LGIC（配体门控离子通道）的重要超家族，其包括乙酰胆碱、5-HT 3（5-羟色胺; S-HT 3受体）、甘氨酸和GABA（γ-氨基丁酸; GABA（A）受体）的受体。在过去的几年里，人们对Cys环超家族的结构及其对通道功能的影响有了广泛的了解，从而提出了关于离子通道如何响应激动剂结合而打开和关闭的令人兴奋的新建议。通道开放是由激动剂与离散结合口袋的细胞外缔合引发的，导致剧烈的构象变化，最终导致中心离子孔的开放。通道结构的重要性在通道功能的变构调节中得到了例证，通过将其他分子结合到通道上的不同位点，这对它们的功能施加了额外的控制水平。随后的构象变化（门控）导致通道开放和离子转运。在通道孔打开之后，离子选择性由离子孔中和周围的受体结构决定。作为最终的控制水平，细胞质决定因素控制离子流入细胞的大小（电导）。因此，Cys环受体是复杂的分子马达，具有运动部件，其可以跨越质膜传递细胞外信号。一旦了解了所有的机械运动，就有可能设计出复杂的治疗药物来调节它们的活性，或者至少能够将分子生物学投入工作！
The Cys-loop receptors constitute an important superfamily of LGICs (ligand-gated ion channels) comprising receptors for acetylcholine, 5-HT3 (5-hydroxytryptamine; S-HT3 receptors), glycine and GABA (gamma-amino-butyric acid; GABA(A) receptors). A vast knowledge of the structure of the Cys-loop superfamily and its impact on channel function have been accrued over the last few years, leading to exciting new proposals on how ion channels open and close in response to agonist binding. Channel opening is initiated by the extracellular association of agonists to discrete binding pockets, leading to dramatic conformational changes, culminating in the opening of a central ion pore. The importance of channel structure is exemplified in the allosteric modulation of channel function by the binding of other molecules to distinct sites on the channel, which exerts an additional level of control on their function. The subsequent conformational changes (gating) lead to channel opening and ion transport. Following channel pore opening, ion selectivity is determined by receptor structure in, and around, the ion pore. As a final level of control, cytoplasmic determinants control the magnitude (conductance) of ion flow into the cell. Thus the Cys-loop receptors are complex molecular motors, with moving parts, which can transduce extracellular signals across the plasma membrane. once the full mechanical motions involved are understood, it may be possible to design sophisticated therapeutic agents to modulate their activity, or at least be able to throw a molecular spanner into the works!