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Vol. 58, Issue 3, 591-600, September 2000
ICAgen Inc., Durham, North Carolina
Retigabine [N-(2-amino-4-[fluorobenzylamino]-phenyl)
carbamic acid; D-23129] is a novel anticonvulsant, unrelated to
currently available antiepileptic agents, with activity in a broad
range of seizure models. In the present study, we sought to determine whether retigabine could enhance current through M-like currents in
PC12 cells and KCNQ2/Q3 K+ channels expressed in Chinese
hamster ovary cells (CHO-KCNQ2/Q3). In differentiated PC12 cells,
retigabine enhanced a linopirdine-sensitive current. The effect of
retigabine was associated with a slowing of M-like tail current
deactivation in these cells. Retigabine (0.1 to 10 µM) induced a
potassium current and hyperpolarized CHO cells expressing KCNQ2/Q3
cells but not in wild-type cells. Retigabine-induced currents in
CHO-KCNQ2/Q3 cells were inhibited by 60.6 ± 11%
(n = 4) by the KCNQ2/Q3 blocker, linopirdine (10 µM), and 82.7 ± 5.4% (n = 4) by
BaCl2 (10 mM). The mechanism by which retigabine enhanced
KCNQ2/Q3 currents involved large, drug-induced, leftward shifts in the
voltage dependence of channel activation (
33.1 ± 2.6 mV,
n = 4, by 10 µM retigabine). Retigabine shifted the voltage dependence of channel activation with an EC50
value of 1.6 ± 0.3 µM (slope factor was 1.2 ± 0.1, n = 4 to 5 cells per concentration). Retigabine
(0.1 to 10 µM) also slowed the rate of channel deactivation,
predominantly by increasing the contribution of a slowly deactivating
tail current component. Our findings identify KCNQ2/Q3 channels as a
molecular target for retigabine and suggest that activation of KCNQ2/Q3
channels may be responsible for at least some of the anticonvulsant
activity of this agent.
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