The relative potencies of dendrotoxins as blockers of the cloned voltage-gated K+ channel, mKv1.1 (MK-1), when stably expressed in Chinese hamster ovary cells.
1. The mKv1.1 voltage-gated K+ channel has been expressed stably in Chinese hamster ovary cells and whole-cell currents recorded by the patch-clamp method. 2. A range of structurally related peptide toxins (dendrotoxins) from the venom of green mamba (Dendroaspis angusticeps) and black mamba (Dendroaspis polylepis polylepis) snakes were tested for mKv1.1 channel blocking activity. Their potencies were compared based on EC50s derived from their respective concentration-inhibition relationships. 3. The rank order of potency, thus determined was: Toxin K > 7-dendrotoxin(7-Dtx) > delta-Dtx > Toxin I = alpha-Dtx > beta-Dtx. 4. Block was independent of voltage and no effects of the toxins on the kinetics of activation were observed. These results are consistent with a mechanism involving the block of closed channels. 5. A wide range of activity was observed even between toxins with an extremely high degree of sequence homology. Toxin K, in particular was an exquisitely potent blocker of the mKv1.1 channel, having an EC50 of 30 pM compared with 1.8 nM for delta-Dtx in spite of 95% sequence identity.
Owen
D G
DG
Wyeth Research UK, Berkshire, London.
Hall
A
A
Stephens
G
G
Stow
J
J
Robertson
B
B
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers
D004546:Elapid Venoms; D009498:Neurotoxins; D026902:Potassium Channel Blockers; C020273:dendrotoxin