BLOCK BY 4-AMINOPYRIDINE OF A K(V)1.2 DELAYED RECTIFIER K+ CURRENT EXPRESSED IN XENOPUS OOCYTES

Citation
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
Citations number
41
Categorie Soggetti
Physiology
Journal title
ISSN journal
00223751
Volume
481
Issue
3
Year of publication
1994
Pages
571 - 584
Database
ISI
SICI code
0022-3751(1994)481:3<571:BB4OAK>2.0.ZU;2-V
Abstract
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.