MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on August 24, 2007; DOI: 10.1124/mol.107.039057

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.039057v1
72/5/1220    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cohen, L.
Right arrow Articles by Gurevitz, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cohen, L.
Right arrow Articles by Gurevitz, M.


Received for publication June 14, 2007.
Revised August 23, 2007.
Accepted for publication August 23, 2007.

Mammalian skeletal muscle voltage-gated sodium channels are affected by scorpion depressant 'insect-selective' toxins when preconditioned

Lior Cohen 1, Yael Troub 1, Michael Turkov 1, Nicolas Gilles 2, Nitza Ilan 1, Morris Benveniste 3, Dalia Gordon 1, Michael Gurevitz 4*

1 Tel Aviv University 2 CEA Saclay 3 Morehouse School of Medicine, Atlanta 4 Tel Aviv university

* Address correspondence to: E-mail: mamgur{at}post.tau.ac.il

Abstract

Amongst scorpion {beta}- and {alpha}-toxins that modify the activation and inactivation of voltage-gated sodium channels (Navs), depressant beta-toxins have traditionally been classified as anti-insect selective on the basis of toxicity assays and lack of binding and effect on mammalian Navs. Here we show that the depressant {beta}-toxins LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus (Lqh) bind in nM affinity to receptor site-4 on rat skeletal muscle Navs, but their effect on the gating properties can be viewed only after channel preconditioning, such as that rendered by a long depolarizing prepulse. This observation explains the lack of toxicity when depressant toxins are injected to mice. However, when the muscle channel rNav1.4 expressed in Xenopus oocytes was modulated by the site-3 {alpha}-toxin Lqh{alpha}IT, LqhIT2 was capable of inducing a negative shift in the voltage-dependence of activation following a short prepulse, as was shown for other {beta}-toxins. These unprecedented results suggest that depressant toxins may have a toxic impact on mammals in the context of the complete scorpion venom. To assess whether LqhIT2 and Lqh-dprIT3 interact with the insect and rat muscle channels in a similar manner we examined the role of Glu24, a conserved 'hot spot' at the bioactive surface of {beta}-toxins. Whereas substitutions E24A/N abolished the activity of both LqhIT2 and Lqh-dprIT3 at insect Navs, they increased the affinity of the toxins for rat skeletal muscle channels. This result implies that depressant toxins interact differently with the two channel types and that substitution of Glu24 is key for converting toxin selectivity.


Key words: Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches, Receptor binding studies, Protein targets


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
L. Cohen, N. Lipstein, I. Karbat, N. Ilan, N. Gilles, R. Kahn, D. Gordon, and M. Gurevitz
Miniaturization of Scorpion {beta}-Toxins Uncovers a Putative Ancestral Surface of Interaction with Voltage-gated Sodium Channels
J. Biol. Chem., May 30, 2008; 283(22): 15169 - 15176.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics