Tityustoxin-K alpha, a structurally novel and highly potent K+ channel peptide toxin, interacts with the alpha-dendrotoxin binding site on the cloned Kv1.2 K+ channel.
The interaction between two nonhomologous K+ channel toxins, Tityus serrulatus (scorpion) toxin tityustoxin-K alpha (TsTX-K alpha) and Dendroaspis angusticeps (snake) toxin dendrotoxin (alpha-DTX), was investigated on K+ currents in B82 fibroblast cells transformed to express the Kv1.2 K+ channel. As demonstrated previously, alpha-DTX was a potent blocker of the K+ current (Kd, 2.8 nM). Recombinant TsTX-K alpha produced a similar block of the current but was 1 order of magnitude more potent (Kd, 0.21 nM). TsTX-K alpha did not affect the kinetic properties of the current or its voltage dependence of activation. Experiments with excised and cell-attached patch recordings demonstrated that TsTX-K alpha blocks the K+ channel by binding to an extracellular site. In the presence of TsTX-K alpha the blocking potency of alpha-DTX was reduced, whereas the potency of 4-aminopyridine, which also blocks the channel, was unaffected. alpha-DTX caused a rightward shift in the scaled concentration-response curve for TsTX-K alpha, the magnitude of which was reasonably well predicted by a model in which there is a competitive interaction between the two peptide toxins. We conclude that TsTX-K alpha and alpha-DTX block the Kv1.2 K+ channel by binding to the same or closely related sites.
Werkman
T R
TR
Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Gustafson
T A
TA
Rogowski
R S
RS
Blaustein
M P
MP
Rogawski
M A
MA
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000378:metabolism / Q000494:pharmacology*; D004594:Electrophysiology; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012604:Scorpion Venoms / Q000378:metabolism / Q000494:pharmacology*
D004546:Elapid Venoms; D009498:Neurotoxins; D015221:Potassium Channels; D011994:Recombinant Proteins; D012604:Scorpion Venoms; C003609:tityustoxin; C020273:dendrotoxin