A Marine Snail Neurotoxin Shares with Scorpion Toxins a Convergent Mechanism of Blockade on the Pore of Voltage-gated K Channels

Garcia, E., Scanlon, M. and Naranjo, D. (1999) A Marine Snail Neurotoxin Shares with Scorpion Toxins a Convergent Mechanism of Blockade on the Pore of Voltage-gated K Channels. Journal of General Physiology, 114 1: 141-157. doi:10.1085/jgp.114.1.141

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Author Garcia, E.
Scanlon, M.
Naranjo, D.
Title A Marine Snail Neurotoxin Shares with Scorpion Toxins a Convergent Mechanism of Blockade on the Pore of Voltage-gated K Channels
Journal name Journal of General Physiology   Check publisher's open access policy
ISSN 0022-1295
Publication date 1999-07
Sub-type Article (original research)
DOI 10.1085/jgp.114.1.141
Open Access Status File (Publisher version)
Volume 114
Issue 1
Start page 141
End page 157
Total pages 17
Place of publication USA
Publisher Rockfeller Univ. Press
Collection year 1999
Language eng
Subject C1
780105 Biological sciences
270199 Biochemistry and Cell Biology not elsewhere classified
Abstract kappa-Conotoxin-PVIIA (kappa-PVIIA) belongs to a family of peptides derived from a hunting marine snail that tar gets to a wide variety of ion channels and receptors. kappa-PVIIA is a small, structurally constrained, 27-residue peptide that inhibits voltage-gated K channels. Three disulfide bonds shape a characteristic four-loop folding. The spatial localization of positively charged residues in K-PVIIA exhibits strong structural mimicry to that of charybdotoxin, a scorpion toxin that occludes the pore of K channels. Me studied the mechanism by which this peptide inhibits Shaker, K channels expressed in Xenopus oocytes with the N-type inactivation removed. Chronically applied to whole oocytes or outside-out patches, kappa-PVIIA inhibition appears as a voltage-dependent relaxation in response to the depolarizing pulse used to activate the channels. At any applied voltage, the relaxation rare depended linearly on the toxin concentration, indicating a bimolecular stoichiometry. Time constants and voltage dependence of the current relaxation produced by chronic applications agreed with that of rapid applications to open channels. Effective valence of the voltage dependence, z delta, is similar to 0.55 and resides primarily in the rare of dissociation from the channel, while the association rate is voltage independent with a magnitude of 10(7)-10(8) M-1 s(-1), consistent with diffusion-limited binding. Compatible with a purely competitive interaction for a site in the external vestibule, tetraethylammonium, a well-known Ii-pore blocker, reduced kappa-PVIIA's association rate only. Removal of internal K+ reduced, but did not eliminate, the effective valence of the toxin dissociation rate to a value <0.3. This trans-pore effect suggests that: (a) as in the alpha-KTx, a positively changed side chain, possibly a Lys, interacts electrostatically with ions residing inside the Shaker pore, and (b) a part of the toxin occupies an externally accessible K+ binding site, decreasing the degree of pore occupancy by permeant ions, We conclude that, although evolutionarily distant to scorpion toxins, kappa-PVIIA shares with them a remarkably similar mechanism of inhibition of K channels.
Keyword Physiology
Pore Blockade
Patch Clamp
Xenopus Oocyte
Conus Venom
Shaker K Channel
Shaker Potassium Channels
Kappa-conotoxin Pviia
Phase Peptide-synthesis
3-dimensional Structure
Charybdotoxin Block
External Cations
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 24 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 10 Jun 2008, 14:40:17 EST