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Molecular Pharmacology

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Research ArticleArticle

Maurotoxin: A Potent Inhibitor of Intermediate Conductance Ca2+-Activated Potassium Channels

N. A. Castle, D. O. London, C. Creech, Z. Fajloun, J. W. Stocker and J.-M. Sabatier
Molecular Pharmacology February 2003, 63 (2) 409-418; DOI: https://doi.org/10.1124/mol.63.2.409
N. A. Castle
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D. O. London
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C. Creech
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Z. Fajloun
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J. W. Stocker
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J.-M. Sabatier
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Abstract

Maurotoxin, a 34-amino acid toxin from Scorpio maurusscorpion venom, was examined for its ability to inhibit cloned human SK (SK1, SK2, and SK3), IK1, and Slo1 calcium-activated potassium (KCa) channels. Maurotoxin was found to produce a potent inhibition of Ca2+-activated 86Rb efflux (IC50, 1.4 nM) and inwardly rectifying potassium currents (IC50, 1 nM) in CHO cells stably expressing IK1. In contrast, maurotoxin produced no inhibition of SK1, SK2, and SK3 small-conductance or Slo1 large-conductance KCa channels at up to 1 μM in physiologically relevant ionic strength buffers. Maurotoxin did inhibit 86Rb efflux (IC50, 45 nM) through, and 125I-apamin binding (Ki, 10 nM) to SK channels in low ionic strength buffers (i.e., 18 mM sodium, 250 mM sucrose), which is consistent with previous reports of inhibition of apamin binding to brain synaptosomes. Under similar low ionic strength conditions, the potency for maurotoxin inhibition of IK1 increased by ∼100-fold (IC50, 14 pM). In agreement with its ability to inhibit recombinant IK1 potassium channels, maurotoxin was found to potently inhibit the Gardos channel in human red blood cells and to inhibit the KCa in activated human T lymphocytes without affecting the voltage-gated potassium current encoded by Kv1.3. Maurotoxin also did not inhibit Kv1.1 potassium channels but potently blocked Kv1.2 (IC50, 0.1 nM). Mutation analysis indicates that similar amino acid residues contribute to the blocking activity of both IK1 and Kv1.2. The results from this study show that maurotoxin is a potent inhibitor of the IK1 subclass of KCa potassium channels and may serve as a useful tool for further defining the physiological role of this channel subtype.

Footnotes

  • Parts of this work have been published in abstract form (Castle et al., 2001).

  • Abbreviations:
    MTX
    maurotoxin
    SK
    small-conductance
    IK
    intermediate conductance
    CHO
    Chinese hamster ovary
    BSA
    bovine serum albumin
    RBC
    red blood cells
    Fmoc
    N-α-fluorenylmethyloxycarbonyl
    TFA
    trifluoroacetic acid
    • Received June 28, 2002.
    • Accepted November 12, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

Maurotoxin: A Potent Inhibitor of Intermediate Conductance Ca2+-Activated Potassium Channels

N. A. Castle, D. O. London, C. Creech, Z. Fajloun, J. W. Stocker and J.-M. Sabatier
Molecular Pharmacology February 1, 2003, 63 (2) 409-418; DOI: https://doi.org/10.1124/mol.63.2.409

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Research ArticleArticle

Maurotoxin: A Potent Inhibitor of Intermediate Conductance Ca2+-Activated Potassium Channels

N. A. Castle, D. O. London, C. Creech, Z. Fajloun, J. W. Stocker and J.-M. Sabatier
Molecular Pharmacology February 1, 2003, 63 (2) 409-418; DOI: https://doi.org/10.1124/mol.63.2.409
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