Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel.
The effect of clofilium on potassium conductance was studied in excised membrane patches from Chinese hamster ovary cells stably transfected with the Kv1.5/hPCN1 delayed rectifier K+ channel gene. Bath application of clofilium resulted in current inhibition, displaying concentration-dependent acceleration of the apparent channel inactivation in both outside-out and inside-out patches. The steady state half-inhibition concentration in inside-out patches was 140 +/- 80 nM (n = 10), which was less than the half-inhibition concentration of 840 +/- 390 nM (n = 10) observed in outside-out patches. Clofilium accelerated apparent current inactivation but did not influence the kinetics of current activation or deactivation. The rate of onset of channel block induced by clofilium was not voltage dependent. In contrast, the rate of recovery from channel block was slower at more hyperpolarized membrane potentials. Elevation of extracellular K+ levels accelerated recovery from channel block without influencing the rate of onset of block. These data suggest that clofilium may induce channel block by an "activation trap" mechanism. Clofilium may be trapped near the conductivity pore so that permeating K+ ions promote recovery from clofilium-induced block.
Malayev
A A
AA
Department of Neurology, University of Chicago, Illinois 60637.
Nelson
D J
DJ
Philipson
L H
LH
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability; D006224:Cricetinae; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000493:pharmacokinetics / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; C022799:clofilium; D011188:Potassium