Local and Global Ligand-Induced Changes in the Structure of the GABAAReceptor

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Abstract
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 α1 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 β2 subunit 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 γ2 subunit altered the fluorescence changes of α1-subunit labels and eliminated them in β2-subunit labels. Thus, the ligand-induced structural changes in the GABAA receptor can extend over considerable distances or remain highly localized, depending upon subunit composition and ligand.