Alpha-conotoxins ImI and ImII. Similar alpha 7 nicotinic receptor antagonists act at different sites

J Biol Chem. 2003 Jan 10;278(2):757-64. doi: 10.1074/jbc.M204565200. Epub 2002 Oct 15.

Abstract

A novel conotoxin, alpha-conotoxin ImII (alpha-CTx ImII), identified from Conus imperialis venom ducts, was chemically synthesized. A previously characterized C. imperialis conotoxin, alpha-conotoxin ImI (alpha-CTx ImI), is closely related; 9 of 12 amino acids are identical. Both alpha-CTx ImII and alpha-CTx ImI functionally inhibit heterologously expressed rat alpha7 nAChRs with similar IC(50) values. Furthermore, the biological activities of intracranially applied alpha-CTx ImI and alpha-CTx ImII are similar over the same dosage range, and are consistent with alpha7 nAChR inhibition. However, unlike alpha-CTx ImI, alpha-CTx ImII was not able to block the binding of alpha-bungarotoxin to alpha7 nAChRs. alpha-Conotoxin ImI and alpha-bungarotoxin-binding sites have been well characterized as overlapping and located at the cleft between adjacent nAChR subunits. Because alpha-CTx ImI and alpha-CTx ImII share extensive sequence homology, the inability of alpha-CTx ImII to compete with alpha-BgTx is surprising. Furthermore, functional studies in oocytes indicate that there is no overlap between functional binding sites of alpha-CTx ImI and alpha-CTx ImII. Like alpha-CTx ImI, the block by alpha-CTx ImII is voltage-independent. Thus, alpha-CTx ImII represents a probe for a novel antagonist binding site, or microsite, on the alpha7 nAChR.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Binding, Competitive
  • Bungarotoxins / metabolism
  • Conotoxins / chemistry
  • Conotoxins / pharmacology*
  • Molecular Sequence Data
  • Nicotinic Antagonists / pharmacology*
  • Polymerase Chain Reaction
  • Rats
  • Receptors, Nicotinic / metabolism
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT3

Substances

  • Bungarotoxins
  • Conotoxins
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • alpha-conotoxin ImII, Conus imperialis
  • alpha-conotoxin ImI