Molecular mechanisms of K+ channel blockade: 4-aminopyridine interaction with a cloned cardiac transient K+ (Kv1.4) channel.
We studied the blocking effects of 4-aminopyridine (4-AP) on a Kv1.4 K+ channel. A permanently charged 4-AP derivative only produced block when applied intracellularly. 4-AP block accumulated from pulse to pulse indicating trapping of 4-AP in deactivated channels. For long trains of depolarizing pulses, 4-AP block increased with decreasing pulse duration. This increase took many pulses (> 10) to accumulate and was relieved by two to three subsequent pulses of 500 msec duration. We conclude that the time- and voltage-dependence of 4-AP block can not be accounted for solely by either simple pure open channel or pure closed channel blocking schemes. We propose that the data can be explained by a model in which 4-AP binding is most stable when the channel has a symmetric arrangement in the binding regions.
Rasmusson
R L
RL
Department of Biomedical Engineering, Medicine Duke University, Durham, NC 27710, USA.
Zhang
Y
Y
Campbell
D L
DL
Comer
M B
MB
Castellino
R C
RC
Liu
S
S
Morales
M J
MJ
Strauss
H C
HC
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004594:Electrophysiology; D005289:Ferrets; D015640:Ion Channel Gating / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D014982:Xenopus laevis
D018076:DNA, Complementary; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015761:4-Aminopyridine