An ion selectivity filter in the extracellular domain of Cys-loop receptors reveals determinants for ion conductance

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

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Neurotransmitter binding to Cys-loop receptors promotes a prodigious transmembrane flux of several million ions/s, but to date, structural determinants of ion flux have been identified flanking the membrane-spanning region. Using x-ray crystallography, sequence analysis, and single-channel recording, we identified a novel determinant of ion conductance near the point of entry of permeant ions. Co-crystallization of acetylcholine-binding protein with sulfate anions revealed coordination of SO42- with a ring of lysines at a position equivalent to 24 Å above the lipid membrane in homologous Cys-loop receptors. Analysis of multiple sequence alignments revealed that residues equivalent to the ring of lysines are negatively charged in cation-selective receptors but are positively charged in anion-selective receptors. Charge reversal of side chains at homologous positions in the nicotinic receptor from the motor end plate decreases unitary conductance up to 80%. Selectivity filters stemming from transmembrane α-helices have similar pore diameters and compositions of amino acids. These findings establish that when the channel opens under a physiological electrochemical gradient, permeant ions are initially stabilized within the extracellular vestibule of Cys-loop receptors, and this stabilization is a major determinant of ion conductance.

Original languageEnglish (US)
Pages (from-to)36066-36070
Number of pages5
JournalJournal of Biological Chemistry
Volume283
Issue number52
DOIs
StatePublished - Dec 26 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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