Three new toxins from the scorpion Pandinus imperator selectively block certain voltage-gated K+ channels

Robert S. Rogowski, John H. Collins, Thomas J. O'Neill, Thomas A. Gustafson, Taco R. Werkman, Michael A Rogawski, Todd C. Tenenholz, David J. Weber, Mordecai P. Blaustein

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37 Scopus citations


Three 35-amino acid peptide K+ channel toxins (pandinotoxins) were purified from the venom of the scorpion Pandinus imperator: the toxins are designated pandinotoxin (PiTX)-Kα, PiTX-Kβ, and PiTX-Kγ. In an 86Rb tracer flux assay on rat brain synaptosomes, all three toxins selectively blocked the component of the K+-stimulated 86Rb efflux that corresponds to a voltage-gated, rapidly inactivating (A-type) K+ current (IC50 = 6, 42, and 100 nM, respectively). These toxins blocked neither the noninactivating component of the K+-stimulated 86Rb efflux (corresponding to a delayed rectifier) nor the Ca2+-dependent component of the 86Rb efflux (i.e., a Ca2+-activated K+ current) in these terminals. PiTX-Kα, which was expressed by recombinant methods, also blocked the Kv1.2 channel expressed in fibroblasts (IC50 = 32 pM). PiTX-Kα and PiTX-Kβ have identical amino acid sequences except for the seventh amino acid: a proline in PiTX-Kα, and a glutamic acid in PiTX-Kβ. They have substantial sequence homology, especially at the carboxyl termini, with another scorpion toxin, charybdotoxin (ChTX), which blocks both the Ca2+-activated and the rapidly inactivating, K+-stimulated 86Rb efflux components in synaptosomes and the Kv1.2 channel. PiTX-Kγ, however, has much less sequence homology. Conserved in all four toxins are three identically positioned disulfide bridges; an asparagine at position 30; and positive charges at positions 27, 31, and 34 (based on ChTX numbering). PiTX-Kγ is novel in that it has a fourth pair of cysteines. The PiTX structures were computer simulated, using ChTX as a model. We speculate that the three-dimensional structures of all three PiTXs resemble that of ChTX: a β-sheet at the carboxyl terminus, containing three cysteines, is linked to the central α-helix by two disulfide bridges (C17- C35 and C13-C33) and to an extended amino-terminal fragment by the third disulfide bridge (C7-C28). Further analysis of the three-dimensional structures reveals differences that may help to explain the selectivity and affinity differences of these toxins.

Original languageEnglish (US)
Pages (from-to)1167-1177
Number of pages11
JournalMolecular Pharmacology
Issue number5
StatePublished - Nov 1996
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology


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