Charybdotoxin is a new member of the K+ channel toxin family that includes dendrotoxin I and mast cell degranulating peptide.
A polypeptide was identified in the venom of the scorpion Leiurus quinquestriatus hebraeus by its potency to inhibit the high-affinity binding of the radiolabeled snake venom toxin dendrotoxin I (125I-DTX1) to its receptor site. It has been purified, and its properties investigated by different techniques were found to be similar to those of MCD and DTXI, two polypeptide toxins active on a voltage-dependent K+ channel. However, its amino acid sequence was determined, and it was shown that this toxin is in fact charybdotoxin (ChTX), a toxin classically used as a specific tool to block one class of Ca2+-activated K+ channels. ChTX, DTXI, and MCD are potent convulsants and are highly toxic when injected intracerebroventricularly in mice. Their toxicities correlate well with their affinities for their receptors in rat brain. These three structurally different toxins release [3H]GABA from preloaded synaptosomes, the efficiency order being DTXI greater than ChTX greater than MCD. Both binding and cross-linking experiments of ChTX to rat brain membranes and to the purified MCD/DTXI binding protein have shown that the alpha-subunit (Mr = 76K-78K) of the MCD/DTXI-sensitive K+ channel protein also contains the ChTX binding sites. Binding sites for DTXI, MCD, and ChTX are in negative allosteric interaction. Our results show that charybdotoxin belongs to the family of toxins which already includes the dendrotoxins and MCD, which are blockers of voltage-sensitive K+ channels. ChTX is clearly not selective for Ca2+-activated K+ channel.
Schweitz
H
H
Centre de Biochimie, Centre National de la Recherche Scientifique, Université de Nice, France.
Bidard
J N
JN
Maes
P
P
Lazdunski
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018999:Charybdotoxin; D004546:Elapid Venoms / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000633:toxicity; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008407:Mast Cells; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D012604:Scorpion Venoms / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000633:toxicity; D012605:Scorpions; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D004546:Elapid Venoms; D015221:Potassium Channels; D012604:Scorpion Venoms; D018999:Charybdotoxin; C020273:dendrotoxin