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Coupling of agonist binding to channel gating in the GABAA receptor

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  • Thomas L. Kash

    (Cornell University)

  • Andrew Jenkins

    (Cornell University)

  • Jill C. Kelley

    (Cornell University)

  • James R. Trudell

    (Stanford University)

  • Neil L. Harrison

    (Cornell University)

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.

Suggested Citation

  • Thomas L. Kash & Andrew Jenkins & Jill C. Kelley & James R. Trudell & Neil L. Harrison, 2003. "Coupling of agonist binding to channel gating in the GABAA receptor," Nature, Nature, vol. 421(6920), pages 272-275, January.
    • Handle: RePEc:nat:nature:v:421:y:2003:i:6920:d:10.1038_nature01280
    DOI: 10.1038/nature01280
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    Cited by:

    1. Xiaolin Cheng & Hailong Wang & Barry Grant & Steven M Sine & J Andrew McCammon, 2006. "Targeted Molecular Dynamics Study of C-Loop Closure and Channel Gating in Nicotinic Receptors," PLOS Computational Biology, Public Library of Science, vol. 2(9), pages 1-12, September.
    2. Wenjun Zheng & Anthony Auerbach, 2011. "Decrypting the Sequence of Structural Events during the Gating Transition of Pentameric Ligand-Gated Ion Channels Based on an Interpolated Elastic Network Model," PLOS Computational Biology, Public Library of Science, vol. 7(1), pages 1-10, January.

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