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

Steven M Sine, Hai Long Wang, Scott Hansen, Palmer Taylor

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 rapid and charge-selective flux, we used all atom molecular 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.

Original languageEnglish (US)
Pages (from-to)70-76
Number of pages7
JournalJournal of Molecular Neuroscience
Volume40
Issue number1-2
DOIs
StatePublished - Jan 2010

Fingerprint

Cysteine Loop Ligand-Gated Ion Channel Receptors
Cations
Ions
Nicotinic Receptors
Molecular Dynamics Simulation
Sulfates
Anions
Muscles
X Ray Crystallography
Lipid Bilayers
Membrane Potentials
Acetylcholine
Carrier Proteins
Water

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

On the origin of ion selectivity in the Cys-loop receptor family. / Sine, Steven M; Wang, Hai Long; Hansen, Scott; Taylor, Palmer.

In: Journal of Molecular Neuroscience, Vol. 40, No. 1-2, 01.2010, p. 70-76.

Research output: Contribution to journalArticle

Sine, Steven M ; Wang, Hai Long ; Hansen, Scott ; Taylor, Palmer. / On the origin of ion selectivity in the Cys-loop receptor family. In: Journal of Molecular Neuroscience. 2010 ; Vol. 40, No. 1-2. pp. 70-76.
@article{b6e41181ee3743148c95f45a7f1ff7fa,
title = "On the origin of ion selectivity in the Cys-loop receptor family",
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 rapid and charge-selective flux, we used all atom molecular 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.",
keywords = "Acetylcholine binding protein, Cys-loop receptor family, Ion conductance and selectivity, Molecular dynamics simulation, Single channel recording",
author = "Sine, {Steven M} and Wang, {Hai Long} and Scott Hansen and Palmer Taylor",
year = "2010",
month = "1",
doi = "10.1007/s12031-009-9260-1",
language = "English (US)",
volume = "40",
pages = "70--76",
journal = "Journal of Molecular Neuroscience",
issn = "0895-8696",
publisher = "Humana Press",
number = "1-2",

}

TY - JOUR

T1 - On the origin of ion selectivity in the Cys-loop receptor family

AU - Sine, Steven M

AU - Wang, Hai Long

AU - Hansen, Scott

AU - Taylor, Palmer

PY - 2010/1

Y1 - 2010/1

N2 - 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 rapid and charge-selective flux, we used all atom molecular 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.

AB - 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 rapid and charge-selective flux, we used all atom molecular 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.

KW - Acetylcholine binding protein

KW - Cys-loop receptor family

KW - Ion conductance and selectivity

KW - Molecular dynamics simulation

KW - Single channel recording

UR - http://www.scopus.com/inward/record.url?scp=75049085160&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=75049085160&partnerID=8YFLogxK

U2 - 10.1007/s12031-009-9260-1

DO - 10.1007/s12031-009-9260-1

M3 - Article

VL - 40

SP - 70

EP - 76

JO - Journal of Molecular Neuroscience

JF - Journal of Molecular Neuroscience

SN - 0895-8696

IS - 1-2

ER -