Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine

J Neurosci. 2001 Aug 1;21(15):5535-45. doi: 10.1523/JNEUROSCI.21-15-05535.2001.


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 EC(50) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anticonvulsants / pharmacology*
  • CHO Cells
  • Carbamates / pharmacology*
  • Cells, Cultured
  • Cricetinae
  • Humans
  • Indoles / pharmacology
  • Ion Transport / drug effects
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Muscarinic Agonists / pharmacology
  • Neurons / cytology
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Phenylenediamines / pharmacology*
  • Potassium / metabolism
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism
  • Superior Cervical Ganglion
  • Sympathetic Nervous System / cytology
  • Sympathetic Nervous System / metabolism
  • Transfection


  • Anticonvulsants
  • Carbamates
  • Indoles
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • KCNQ3 Potassium Channel
  • KCNQ3 protein, human
  • KCNQ4 protein, human
  • Kcnq1 protein, rat
  • Kcnq2 protein, rat
  • Kcnq3 protein, rat
  • Kcnq4 protein, rat
  • Muscarinic Agonists
  • Phenylenediamines
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Pyridines
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • ezogabine
  • linopirdine
  • Potassium