A hydrophobic gate in an ion channel: The closed state of the nicotinic acetylcholine receptor

Oliver Beckstein, Mark S P Sansom

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the 'Cys-loop' superfamily of ligand-gated ion channels which mediate synaptic neurotransmission, and whose other members include receptors for glycine, γ-aminobutyric acid and serotonin. Cryo-electron microscopy has yielded a three-dimensional structure of the nAChR in its closed state. However, the exact nature and location of the channel gate remains uncertain. Although the transmembrane pore is constricted close to its center, it is not completely occluded. Rather, the pore has a central hydrophobic zone of radius about 3 Å. Model calculations suggest that such a constriction may form a hydrophobic gate, preventing movement of ions through a channel. We present a detailed and quantitative simulation study of the hydrophobic gating model of the nicotinic receptor, in order to fully evaluate this hypothesis. We demonstrate that the hydrophobic constriction of the nAChR pore indeed forms a closed gate. Potential of mean force (PMF) calculations reveal that the constriction presents a barrier of height about 10 kT to the permeation of sodium ions, placing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 Å radius hydrophobic pore can form a functional barrier to the permeation of a 1 Å radius Na+ ion. Using a united-atom force field for the protein instead of an all-atom one retains the qualitative features but results in differing conductances, showing that the PMF is sensitive to the detailed molecular interactions.

Original languageEnglish (US)
Article number007
Pages (from-to)147-159
Number of pages13
JournalPhysical Biology
Volume3
Issue number2
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

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Nicotinic Receptors
Ion Channels
Constriction
Ions
Ligand-Gated Ion Channels
Aminobutyrates
Glycine Receptors
Cryoelectron Microscopy
Synaptic Transmission
Serotonin
Sodium
Proteins

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology
  • Cell Biology

Cite this

A hydrophobic gate in an ion channel : The closed state of the nicotinic acetylcholine receptor. / Beckstein, Oliver; Sansom, Mark S P.

In: Physical Biology, Vol. 3, No. 2, 007, 01.06.2006, p. 147-159.

Research output: Contribution to journalArticle

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