Abstract
NEUROTOXINS that selectively block Na+, K+ or Ca2+ channels have provided valuable information about the functional diversity of the voltage-gated channel superfamily1. For Ca2+ channels, a variety of toxins have been found to block individual channel types2,3. The best-known example is ω-conotoxin-GVIA, a member of a large family of peptide toxins derived from venomous cone snails2,3, which potently and selectively blocks N-type Ca2+ channels4–9, allowing their purification10,11, cellular localization12,13, and the elucidation of their roles in Ca2+ entry14, neurotransmitter release15,16 and neuronal migration17. In contrast to Na+ and K+ channels, little is known about the molecular features that underlie Ca2+-channel susceptibility to toxin block; it is also unknown whether block occurs by direct physical occlusion3 or an action on channel gating18. Here we describe structural determinants of the N-type Ca2+ channel's interaction with ω-conotoxin-GVIA. When chimaeras combining individual motifs from the N-type channel and from a channel insensitive to ω-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 loopbetween 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.
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Ellinor, P., Zhang, JF., Horne, W. et al. Structural determinants of the blockade of N-type calcium channels by a peptide neurotoxin. Nature 372, 272–275 (1994). https://doi.org/10.1038/372272a0
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DOI: https://doi.org/10.1038/372272a0
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