Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels.
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 microM) 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 microM), and 82.7 +/- 5.4% (n = 4) by BaCl(2) (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 microM retigabine). Retigabine shifted the voltage dependence of channel activation with an EC(50) value of 1.6 +/- 0.3 microM (slope factor was 1.2 +/- 0.1, n = 4 to 5 cells per concentration). Retigabine (0.1 to 10 microM) 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.
Wickenden
A D
AD
ICAgen Inc., Durham, North Carolina 27702, USA. awickenden@icagen.com
Yu
W
W
Zou
A
A
Jegla
T
T
Wagoner
P K
PK
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001464:Barium / Q000494:pharmacology; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D006224:Cricetinae; D004347:Drug Interactions; D004594:Electrophysiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D016716:PC12 Cells; D010655:Phenylenediamines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D014162:Transfection
D000927:Anticonvulsants; D002219:Carbamates; D007211:Indoles; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; C496915:Kcnq2 protein, rat; C496918:Kcnq3 protein, rat; D010655:Phenylenediamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C101866:ezogabine; D001464:Barium; C061017:linopirdine; D011188:Potassium