Local and global ligand-induced changes in the structure of the GABA(A) receptor.
Local and global ligand-induced changes in the structure of the GABA(A) receptor.
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局部和整体配体诱导的 GABA(A) 受体结构变化。
DOI：
10.1021/bi060222v
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Jackson,MeyerB
中科院分区：
文献类型：
--
作者：
Muroi,Yukiko;Czajkowski,Cynthia;Jackson,MeyerB
配体门控通道通过由神经递质结合触发的构象转变介导突触传递。这些转换是明确定义的离子电导，但其结构基础是知之甚少。为了探测这些结构上的变化，GABAA受体在异种卵母细胞中表达，并在选定的位点用环境敏感的荧光团标记。在GABA结合口袋E环α 1亚基的两个不同残基上标记，GABA引起的荧光变化符号相反。这种荧光变化模式与亚基界面处GABA结合腔的闭合一致。竞争性拮抗剂SR-95531逆转了这种荧光变化模式，但非竞争性拮抗剂印防己毒素未能引起光学信号。响应GABA（而不是SR-95531），β 2亚基中同源残基的标记显示与α1亚基标记相同的荧光变化模式，表明不同亚基的同源区域中具有可比运动的全局转换。γ 2亚基的掺入改变了α1亚基标记的荧光变化，并消除了β2亚基标记的荧光变化。因此，配体诱导的GABAA受体的结构变化可以延伸相当长的距离或保持高度局部化，这取决于亚基组成和配体。
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, GABAAreceptors were expressed inXenopusoocytes and labeled at selected sites with environment-sensitive fluorophores. With labels at two different residues in the α1subunit 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 β2subunit showed the same pattern of fluorescence change as the α1-subunit labels, indicating a global transition with comparable movements in homologous regions of different subunits. Incorporation of the γ2subunit altered the fluorescence changes of α1-subunit labels and eliminated them in β2-subunit labels. Thus, the ligand-induced structural changes in the GABAAreceptor can extend over considerable distances or remain highly localized, depending upon subunit composition and ligand.