Molecular basis of the charge selectivity of nicotinic acetylcholine receptor and related ligand-gated ion channels

Novartis Found Symp. 1999;225:215-24; discussion 224-30. doi: 10.1002/9780470515716.ch14.

Abstract

Nicotinic acetylcholine receptors are homo- or heteropentameric proteins belonging to the superfamily of receptor channels including the glycine and GABA-A receptors. Affinity labelling and mutagenesis experiments indicated that the M2 transmembrane segment of each subunit lines the ion channel and is coiled into an alpha-helix. Comparison of the M2 sequence of the cation-selective alpha 7 nicotinic receptor to that of the anion-selective alpha 1 glycine receptor identified amino acids involved in charge selectivity. Mutations of the alpha 7 homo-oligomeric receptor within (or near) M2, namely E237A, V251T and a proline insertion P236' were shown to convert the ionic selectivity of alpha 7 from cationic to anionic. Systematic analysis of each of these three mutations supports the notion that the conversion of ionic selectivity results from a local structural reorganization of the 234-238 loop. The 234-238 coiled loop, previously shown to lie near the narrowest portion of the channel, is thus proposed to contribute directly to the charge selectivity filter. A possible functional analogy with the voltage-gated ion channels and related receptors is discussed.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Amino Acid Sequence
  • Anions
  • Cations
  • Electrochemistry
  • Ion Channel Gating*
  • Ligands
  • Molecular Sequence Data
  • Mutation
  • Receptors, Nicotinic / chemistry*

Substances

  • Anions
  • Cations
  • Ligands
  • Receptors, Nicotinic