OSK1 (α-KTx3.7) is a 38-residue toxin cross-linked by three disulphide bridges that was initially isolated from the venom of the Asian scorpion Orthochirus scrobiculosus. OSK1 and several structural analogues were produced by solid-phase chemical synthesis, and were tested for lethality in mice and for their efficacy in blocking a series of 14 voltage-gated and Ca2+-activated K+ channels in vitro. In the present paper, we report that OSK1 is lethal in mice by intracerebroventricular injection, with a LD50 (50% lethal dose) value of 2 μg/kg. OSK1 blocks Kv1.1, Kv1.2, Kv1.3 channels potently and KCa3.1 channel moderately, with IC50 values of 0.6, 5.4, 0.014 and 225 nM respectively. Structural analogues of OSK1, in which we mutated positions 16 (Glu16→Lys) and/or 20 (Lys20→Asp) to amino acid residues that are conserved in all other members of the α-KTx3 toxin family except OSK1, were also produced and tested. Among the OSK1 analogues, [K16,D20]-OSK1 (OSK1 with Glu16→Lys and Lys20→Asp mutations) shows an increased potency on Kv1.3 channel, with an IC50 value of 0.003 nM, without loss of activity on KCa3.1 channel. These data suggest that OSK1 or [K16,D20]-OSK1 could serve as leads for the design and production of new immunosuppressive drugs.
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Research Article|
December 14 2004
K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom
Stéphanie MOUHAT;
Stéphanie MOUHAT
*Laboratoire Cellpep S.A., 13-15 Rue Ledru-Rollin, 13015 Marseille, France
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Violeta VISAN;
Violeta VISAN
†Universität Ulm, Albert Einstein Allee 11, 89081 Ulm, Germany
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S. ANANTHAKRISHNAN;
S. ANANTHAKRISHNAN
‡Department of Medical Pharmacology and Toxicology, University of California, Davis, CA 95616, U.S.A.
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Heike WULFF;
Heike WULFF
‡Department of Medical Pharmacology and Toxicology, University of California, Davis, CA 95616, U.S.A.
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Nicolas ANDREOTTI;
Nicolas ANDREOTTI
*Laboratoire Cellpep S.A., 13-15 Rue Ledru-Rollin, 13015 Marseille, France
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Stephan GRISSMER;
Stephan GRISSMER
†Universität Ulm, Albert Einstein Allee 11, 89081 Ulm, Germany
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Hervé DARBON;
Hervé DARBON
§AFMB, CNRS UPR 9039, 31 Chemin Joseph Aiguier, 13402 Marseille, France
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Michel DE WAARD;
Michel DE WAARD
∥INSERM U607, CEA, 17 Rue des Martyrs, 38054 Grenoble Cedex 09, France
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Jean-Marc SABATIER
Jean-Marc SABATIER
1
*Laboratoire Cellpep S.A., 13-15 Rue Ledru-Rollin, 13015 Marseille, France
¶CNRS FRE 2738, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France
1To whom correspondence should be addressed (email sabatier.jm@jean-roche.univ-mrs.fr).
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Publisher: Portland Press Ltd
Received:
August 13 2004
Revision Received:
September 20 2004
Accepted:
September 24 2004
Accepted Manuscript online:
September 24 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 385 (1): 95–104.
Article history
Received:
August 13 2004
Revision Received:
September 20 2004
Accepted:
September 24 2004
Accepted Manuscript online:
September 24 2004
Citation
Stéphanie MOUHAT, Violeta VISAN, S. ANANTHAKRISHNAN, Heike WULFF, Nicolas ANDREOTTI, Stephan GRISSMER, Hervé DARBON, Michel DE WAARD, Jean-Marc SABATIER; K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochem J 1 January 2005; 385 (1): 95–104. doi: https://doi.org/10.1042/BJ20041379
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