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On the origin of ion selectivity in the Cys-loop receptor family

Academic Article
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Overview

authors

  • Sine, S. M.
  • Wang, H. L.
  • Hansen, Scott
  • Taylor, P.

publication date

  • 2010

journal

  • Journal of Molecular Neuroscience  Journal

abstract

  • Agonist binding to Cys-loop receptors promotes a large transmembrane ion flux of several million cations or anions per second. To investigate structural bases for the dynamics (MD) simulations, X-ray crystallography, and single channel recording. MD simulations of the muscle nicotinic receptor, imbedded in a lipid bilayer with an applied transmembrane potential, reveal single cation translocation events during transient periods of channel hydration. During the simulation trajectory, cations paused for prolonged periods near several rings of anionic residues projecting from the lumen of the extracellular domain of the receptor, but subsequently the cation moved rapidly through the hydrophobic transmembrane region as the constituent alpha-helices exhibited back and forth rocking motions. Cocrystallization of acetylcholine binding protein with sulfate ions revealed coordination of five sulfates with residues from one of these charged rings; in cation-selective Cys-loop receptors this ring contains negatively charged residues, whereas in anion-selective receptors it contains positively charged residues. In the muscle nicotinic receptor, charge reversal of residues of this ring decreases unitary conductance by up to 80%. Thus in Cys-loop receptors, a series of charged rings along the ion translocation pathway concentrates hydrated ions relative to bulk solution, giving rise to charge selectivity, and then subtle motions of the hydrophobic transmembrane, coupled with transient periods of water filling, enable rapid ion flux.

subject areas

  • Animals
  • Cations
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ion Channel Gating
  • Ion Channels
  • Membrane Lipids
  • Membrane Potentials
  • Neuromuscular Junction
  • Protein Structure, Tertiary
  • Receptors, Nicotinic
  • Synaptic Membranes
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Research

keywords

  • Acetylcholine binding protein
  • Cys-loop receptor family
  • Ion conductance and selectivity
  • Molecular dynamics simulation
  • Single channel recording
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Identity

PubMed Central ID

  • PMC3047408

International Standard Serial Number (ISSN)

  • 0895-8696

Digital Object Identifier (DOI)

  • 10.1007/s12031-009-9260-1

PubMed ID

  • 19728176
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Additional Document Info

start page

  • 70

end page

  • 76

volume

  • 40

issue

  • 1-2

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