Local and Global Ligand-Induced Changes in the Structure of the GABAAReceptor
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, GABA(A) receptors were expressed in Xenopus oocytes and labeled at selected sites with environment-sensitive fluorophores. With labels at two different residues in the alpha1 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 beta2 subunit showed the same pattern of fluorescence change as the alpha1-subunit labels, indicating a global transition with comparable movements in homologous regions of different subunits. Incorporation of the gamma2 subunit altered the fluorescence changes of alpha1-subunit labels and eliminated them in beta2-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.
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- Authors
- Muroi, Y., Czajkowski, C., & Jackson, M. B.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Jackson, Meyer B.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-05-19
- Volume
- 45
- Issue
- 23
- Pages
- 7013-7022
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2114908297
- Cited by
- 46
- References
- 49
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2020: 4 · 2019: 1 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 1 · 2012: 1
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Korea Electric Power Corporation
- National Institute of Neurological Disorders and Stroke (NS34727)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- GABAA receptor, ligand-gated ion channels, GABA binding, conformational change, fluorescence resonance energy transfer, alpha1 subunit, beta2 subunit, gamma2 subunit, SR95531, picrotoxin, subunit interface, synaptic transmission
- MeSH terms
- Animals, Fluorescent Dyes, Ligands, Models, Molecular, Protein Conformation, Receptors, GABA-A, Recombinant Proteins, Spectrometry, Fluorescence, Xenopus laevis, Mutagenesis, Site-Directed, Rats
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