QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leipold, E. Articles by Heinemann, S. H. Search for Related Content PubMed PubMed Citation Articles by Leipold, E. Articles by Heinemann, S. H.

Combinatorial Interaction of Scorpion Toxins Lqh-2, Lqh-3, and LqhIT with Sodium Channel Receptor Sites-3

Research Unit "Molecular and Cellular Biophysics", Medical Faculty of the Friedrich Schiller University Jena, Jena, Germany (E.L., S.L., A.H., S.H.H.); and Department of Plant Sciences, Tel Aviv University, Tel Aviv, Israel (D.G.)

Scorpion -toxins LqhIT, Lqh-2, and Lqh-3 are representatives of three groups of -toxins that differ in their preference for insects and mammals. These -insect, antimammalian, and -like toxins bind to voltage-gated sodium channels and slow down channel inactivation. Sodium channel mutagenesis studies using various -toxins have shown that they interact with receptor site 3, which is composed mainly of a short stretch of amino-acid residues between S3 and S4 of domain 4. Variation in this region results in marked differences between various subtypes of sodium channels with respect to their sensitivity to the three Lqh toxins. We incorporated the S3-S4 linker of domain 4 from hNa_V1.2/hNa_V1.1, hNa_V1.3, hNa_V1.6, and hNa_V1.7 channels as well as individual point mutations into the rNa_V1.4 skeletal muscle sodium channel. Our data show that the affinity of Lqh-3 and LqhIT to sodium channels is markedly determined by an aspartate residue (Asp1428 in rNa_V1.4); when mutated to glutamate, as is present in Na_V1.1–1.3 channels, Lqh-3–channel interactions are abolished. The interaction of Lqh-2 and LqhIT, however, is strongly reduced when a lysine residue (Lys1432 in rNa_V1.4) is replaced by threonine (as in hNa_V1.7), whereas this substitution is without effect for Lqh-3. The influence of Lys1432 on Lqh-2 and LqhIT strongly depends on the context of the Asp/Glu site at position 1428, giving rise to a wide variety of toxicological phenotypes by means of a combinatorial mixing and matching of only a few residues in receptor site 3.

Address correspondence to: Prof. Dr. Stefan H. Heinemann, Molecular and Cellular Biophysics, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747 Jena, Germany. E-mail: stefan.h.heinemann{at}uni-jena.de

This article has been cited by other articles:

				L. Cohen, Y. Troub, M. Turkov, N. Gilles, N. Ilan, M. Benveniste, D. Gordon, and M. Gurevitz Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant "Insect-Selective" Toxins when Preconditioned Mol. Pharmacol., November 1, 2007; 72(5): 1220 - 1227. [Abstract] [Full Text] [PDF]

				L. Cohen, N. Gilles, I. Karbat, N. Ilan, D. Gordon, and M. Gurevitz Direct Evidence That Receptor Site-4 of Sodium Channel Gating Modifiers Is Not Dipped in the Phospholipid Bilayer of Neuronal Membranes J. Biol. Chem., July 28, 2006; 281(30): 20673 - 20679. [Abstract] [Full Text] [PDF]

				W. Ulbricht Sodium Channel Inactivation: Molecular Determinants and Modulation Physiol Rev, October 1, 2005; 85(4): 1271 - 1301. [Abstract] [Full Text] [PDF]