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The Journal of Neuroscience, August 1, 2001, 21(15):5535-5545
Activation of Expressed KCNQ Potassium Currents and Native
Neuronal M-Type Potassium Currents by the Anti-Convulsant Drug
Retigabine
L.
Tatulian1,
P.
Delmas2,
F. C.
Abogadie2, and
D. A.
Brown1
1 Department of Pharmacology and 2 Wellcome
Laboratory for Molecular Pharmacology, University College London,
London WC1E 6BT, United Kingdom
Retigabine [D-23129;
N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid
ethyl ester] is a novel anticonvulsant compound that is now in
clinical phase II development. It has previously been shown to enhance
currents generated by KCNQ2/3 K+ channels
when expressed in Chinese hamster ovary (CHO) cells (Main et al., 2000;
Wickenden et al., 2000). In the present study, we have compared the
actions of retigabine on KCNQ2/3 currents with those on currents
generated by other members of the KCNQ family (homomeric KCNQ1, KCNQ2,
KCNQ3, and KCNQ4 channels) expressed in CHO cells and on the native M
current in rat sympathetic neurons [thought to be generated by KCNQ2/3
channels (Wang et al., 1998)]. Retigabine produced a hyperpolarizing
shift of the activation curves for KCNQ2/3, KCNQ2, KCNQ3, and KCNQ4
currents with differential potencies in the following order: KCNQ3 > KCNQ2/3 > KCNQ2 > KCNQ4, as measured either by the
maximum hyperpolarizing shift in the activation curves or by the
EC50 values. In contrast, retigabine did not enhance
cardiac KCNQ1 currents. Retigabine also produced a hyperpolarizing
shift in the activation curve for native M channels in rat sympathetic
neurons. The retigabine-induced current was inhibited by muscarinic
receptor stimulation, with similar agonist potency but 25% reduced
maximum effect. In unclamped neurons, retigabine produced a
hyperpolarization and reduced the number of action potentials produced
by depolarizing current injections, without change in action potential configuration.
Key words:
potassium channels; KCNQ channels; M channels; sympathetic neurons; retigabine; anti-convulsant
Copyright © 2001 Society for Neuroscience 0270-6474/01/21155535-11$05.00/0
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