Sn. Russell et al., BLOCK BY 4-AMINOPYRIDINE OF A K(V)1.2 DELAYED RECTIFIER K+ CURRENT EXPRESSED IN XENOPUS OOCYTES, Journal of physiology, 481(3), 1994, pp. 571-584
The blocking action of 4-aminopyridine (4-AP) on a delayed rectifier K
(v)1.2 K+ channel expressed in oocytes was investigated at room temper
ature (22 degrees C) and physiological temperature (34 degrees C) usin
g the double-electrode voltage clamp and patch clamp techniques. 2. At
room temperature, 4-AP (100 mu M) inhibition occurred only after acti
vation of current. The rate of onset of block was dependent upon the l
ength of time current was activated by a depolarizing step. Similarly,
removal of block required current activation. The degree of steady-st
ate block by 4-AP was not reduced by increasingly more depolarized ste
p potentials. The degree of steady-state block also did not change ove
r the duration of a 1 s step. 3. When channels were nearly fully inact
ivated, 4-AP produced no additional block of a subsequent depolarizing
step, suggesting that 4-AP did not bind when channels were in the ina
ctivated state. In single channel experiments, 4-AP decreased the mean
open time in a dose-dependent manner but did not alter the single-cha
nnel current amplitude. 4. At 34 degrees C the I-V relationship and in
activation curve shifted to more negative potentials. Increasing the t
emperature to 34 degrees C did not alter the degree of block by 4-AP,
although the rate of onset of block was greatly enhanced. 5. Results s
uggest that 4-AP binds to the open state of the K(v)1.2 channel and is
trapped when the channel closes. 4-AP cannot bind when the channel is
closed or inactivated prior to the addition of the drug. C-type inact
ivation and 4-AP binding to the channel are mutually exclusive. A mode
l for the proposed mechanism of action of 4-AP on the K(v)1.2 channel
is proposed based on experimental data.