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Molecular tuning of fast gating in pentameric ligand-gated ion channels.

Authors
Type
Published Article
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publication Date
Volume
102
Issue
50
Pages
18207–18212
Identifiers
PMID: 16319224
Source
Medline
License
Unknown

Abstract

Neurotransmitters such as acetylcholine (ACh) and glycine mediate fast synaptic neurotransmission by activating pentameric ligand-gated ion channels (LGICs). These receptors are allosteric transmembrane proteins that rapidly convert chemical messages into electrical signals. Neurotransmitters activate LGICs by interacting with an extracellular agonist-binding domain (ECD), triggering a tertiary/quaternary conformational change in the protein that results in the fast opening of an ion pore domain (IPD). However, the molecular mechanism that determines the fast opening of LGICs remains elusive. Here, we show by combining whole-cell and single-channel recordings of recombinant chimeras between the ECD of alpha7 nicotinic receptor (nAChR) and the IPD of the glycine receptor (GlyR) that only two GlyR amino acid residues of loop 7 (Cys-loop) from the ECD and at most five alpha7 nAChR amino acid residues of the M2-M3 loop (2-3L) from the IPD control the fast activation rates of the alpha7/Gly chimera and WT GlyR. Mutual interactions of these residues at a critical pivot point between the agonist-binding site and the ion channel fine-tune the intrinsic opening and closing rates of the receptor through stabilization of the transition state of activation. These data provide a structural basis for the fast opening of pentameric LGICs.

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