Abstract
Neurotransmitters such as acetylcholine and GABA (γ-aminobutyric acid) mediate rapid synaptic transmission by activating receptors belonging to the gene superfamily of ligand-gated ion channels (LGICs)1. These channels are pentameric proteins that function as signal transducers, converting chemical messages into electrical signals2. Neurotransmitters activate LGICs by interacting with a ligand-binding site3,4,5,6,7, triggering a conformational change in the protein that results in the opening of an ion channel8. This process, which is known as ‘gating’, occurs rapidly and reversibly, but the molecular rearrangements involved are not well understood9. Here we show that optimal gating in the GABAA receptor, a member of the LGIC superfamily, is dependent on electrostatic interactions between the negatively charged Asp 57 and Asp 149 residues in extracellular loops 2 and 7, and the positively charged Lys 279 residue in the transmembrane 2–3 linker region of the α1-subunit. During gating, Asp 149 and Lys 279 seem to move closer to one another, providing a potential mechanism for the coupling of ligand binding to opening of the ion channel.
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Acknowledgements
We thank J. Horenstein for advice on crosslinking experiments and the NIH for financial support.
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Kash, T., Jenkins, A., Kelley, J. et al. Coupling of agonist binding to channel gating in the GABAA receptor. Nature 421, 272–275 (2003). https://doi.org/10.1038/nature01280
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DOI: https://doi.org/10.1038/nature01280
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