Structural determinants of the blockade of N-type calcium channels by a peptide neurotoxin

Nature. 1994 Nov 17;372(6503):272-5. doi: 10.1038/372272a0.


Neurotoxins that selectively block Na+, K+ or Ca2+ channels have provided valuable information about the functional diversity of the voltage-gated channel superfamily. For Ca2+ channels, a variety of toxins have been found to block individual channel types. The best-known example is omega-conotoxin-GVIA, a member of a large family of peptide toxins derived from venomous cone snails, which potently and selectively blocks N-type Ca2+ channels, allowing their purification, cellular localization, and the elucidation of their roles in Ca2+ entry, neurotransmitter release and neuronal migration. In contrast to Na+ and K+ channels, little is known about the molecular features that underlie Ca(2+)-channel susceptibility to toxin block; it is also unknown whether block occurs by direct physical occlusion or an action on channel gating. Here we describe structural determinants of N-type Ca2+ channel's interaction with omega-conotoxin-GVIA. When chimaeras combining individual motifs from the N-type channel and from a channel insensitive to omega-conotoxin-GVIA were expressed in Xenopus oocytes, each of the four motifs appeared to contribute to interaction with the toxin. The most dramatic effects on toxin interactions were seen at a single cluster of residues in the large putative extracellular loop between IIIS5 and IIIH5, consistent with a direct pore-blocking mechanism. These results provide a starting point for delineating the architecture of the outer vestibule of the Ca2+ channel.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels / chemistry*
  • Calcium Channels / drug effects*
  • Calcium Channels / genetics
  • Cells, Cultured
  • Humans
  • Molecular Sequence Data
  • Mollusk Venoms / pharmacology*
  • Mutagenesis
  • Neurotoxins / pharmacology*
  • Oocytes
  • Peptides / pharmacology*
  • Protein Conformation
  • Rats
  • Recombinant Fusion Proteins
  • Xenopus
  • omega-Conotoxin GVIA


  • Calcium Channel Blockers
  • Calcium Channels
  • Mollusk Venoms
  • Neurotoxins
  • Peptides
  • Recombinant Fusion Proteins
  • omega-Conotoxin GVIA