Toxins selective for subunit interfaces as probes of nicotinic acetylcholine receptor structure

Palmer Taylor, Hitoshi Osaka, Brian E. Molles, Naoya Sugiyama, Pascale Marchot, Elizabeth J. Ackermann, Siobhan Malany, Joseph J. McArdle, Steven M. Sine, Igor Tsigelny

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The pentameric structure of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The receptor, with its circular order of homologous subunits (αγαδβ), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the αγ and αδ interfaces. By interchanging residues on the γ and δ subunits, and ascertaining how they interact with the α-subunit, determinants forming the binding sites can be delineated. The α-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10 000-fold preference for the αδ over the αγ subunit interface with αε falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for αε over the αγ and αδ interfaces. Finally, the 6700 Da short α-neurotoxin from N. mossambica mossambica shows a 10 000-fold preference for the αγ and αδ interfaces over αε. Selective mutagenesis enables one to also distinguish α-neurotoxin binding at the αγ and αδ subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of receptor structure and conformation.

Original languageEnglish (US)
Pages (from-to)79-83
Number of pages5
JournalJournal of Physiology Paris
Volume92
Issue number2
DOIs
StatePublished - Apr 1998

Keywords

  • Homologous subunits
  • Ligand binding sites
  • Nicotinic acetylcholine receptor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology (medical)

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