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首页> 外文期刊>Biochemistry >Local and global ligand-induced changes in the structure of the GABA(A) receptor
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Local and global ligand-induced changes in the structure of the GABA(A) receptor

机译：局部和全局配体诱导的GABA（A）受体结构变化

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摘要

Ligand-gated channels mediate synaptic transmission through conformational transitions triggered by the binding of neurotransmitters. These transitions are well-defined in terms of ion conductance, but their structural basis is poorly understood. To probe these changes in structure, GABAA receptors were expressed in Xenopus oocytes and labeled at selected sites with environment-sensitive fluorophores. With labels at two different residues in the alpha(1) subunit in loop E of the GABA-binding pocket, GABA elicited fluorescence changes opposite in sign. This pattern of fluorescence changes is consistent with a closure of the GABA-binding cavity at the subunit interface. The competitive antagonist SR-95531 inverted this pattern of fluorescence change, but the noncompetitive antagonist picrotoxin failed to elicit optical signals. In response to GABA ( but not SR-95531), labels at the homologous residues in the, 2 subunit showed the same pattern of fluorescence change as the alpha(1)-subunit labels, indicating a global transition with comparable movements in homologous regions of different subunits. Incorporation of the gamma(2) subunit altered the fluorescence changes of alpha(1)-subunit labels and eliminated them in beta 2-subunit labels. Thus, the ligand-induced structural changes in the GABA(A) receptor can extend over considerable distances or remain highly localized, depending upon subunit composition and ligand.
机译：配体门控通道通过由神经递质的结合触发的构象转变介导突触传递。这些跃迁在离子电导率方面定义明确，但对其结构基础了解甚少。为了探测这些结构变化，GABAA受体在非洲爪蟾卵母细胞中表达，并在选定的位点用环境敏感的荧光团标记。在GABA结合口袋的环E的alpha（1）亚基中两个不同残基处有标记，GABA引起的荧光变化与符号相反。荧光变化的这种模式与在亚基界面处的GABA结合腔的闭合一致。竞争性拮抗剂SR-95531颠倒了这种荧光变化模式，但非竞争性拮抗剂苦瓜毒素未能引发光信号。响应GABA（但不是SR-95531），在2个亚基的同源残基处的标记显示出与alpha（1）-亚基标记相同的荧光变化模式，表明在不同的亚基。合并的gamma（2）亚基改变了alpha（1）-亚基标记的荧光变化，并消除了它们在beta 2-亚基标记中的作用。因此，取决于亚基组成和配体，GABA（A）受体中配体诱导的结构变化可以延伸相当长的距离或保持高度局部化。

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