K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom

Stéphanie Mouhat, Violeta Visan, S. Ananthakrishnan, Heike Wulff, Nicolas Andreotti, Stephan Grissmer, Hervé Darbon, Michel De Waard, Jean Marc Sabatier

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

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 Ca 2+-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 K v 1.1, 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 Kv 1.3 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.

Original languageEnglish (US)
Pages (from-to)95-104
Number of pages10
JournalBiochemical Journal
Volume385
Issue number1
DOIs
StatePublished - Jan 1 2005

Keywords

  • Ca-activated K channel
  • OSK1
  • Peptide synthesis
  • Scorpion toxin
  • Voltage-gated K channel

ASJC Scopus subject areas

  • Biochemistry

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    Mouhat, S., Visan, V., Ananthakrishnan, S., Wulff, H., Andreotti, N., Grissmer, S., Darbon, H., De Waard, M., & Sabatier, J. M. (2005). K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochemical Journal, 385(1), 95-104. https://doi.org/10.1042/BJ20041379