The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site

Neurosci Lett. 2009 Nov 13;465(2):138-42. doi: 10.1016/j.neulet.2009.08.071. Epub 2009 Sep 3.


The mammalian KCNQ (Kv7) gene family is composed of five members (KCNQ1-5). KCNQ2, Q4 and Q5 (KCNQ2-5) channels co-express with KCNQ3 to form heterotetrameric voltage-gated K(+) (KCNQ2-5/3) channels that underlie the endogenous M-current and regulate neuronal excitability in CNS and PNS neurons. Openers of one or a mixture of these channels may be an attractive therapeutic agent for epilepsy and pain. Non-selective KCNQ2-5/3 activators have shown efficacy in pre-clinical and clinical studies. However, more selective pharmacological profiles, including greater KCNQ sub-type-selective activation, could provide efficacy with fewer side effects. One such compound, ICA-27243, sub-type selectively enhances the activation of KCNQ2/3 channels and also exhibits efficacy in pre-clinical anticonvulsant models; Roeloffs et al. (2008) [15]; Wickenden et al. (2008) [27]. The binding site of non-selective KCNQ2-5/3 openers maps to the S5-S6 pore domain and is altered by mutation of a tryptophan residue (Trp236 in KCNQ2, Trp265 in KCNQ3) conserved among KCNQ2-5 channels; Schenzer et al. (2005) [19]; Wuttke et al. (2005) [30]. Here we report that the activity of the KCNQ2/3 selective opener ICA-27243 is not affected by these Trp mutations and does not map to the S5-S6 domain. Rather, the selective activity of ICA-27243 is determined by a novel site within the S1-S4 voltage-sensor domain (VSD) of KCNQ channels. The sub-type-selective activity of ICA-27243 may arise from greater sequence diversity of KCNQ family members within the ICA-27243 binding pocket, allowing for more selective small molecule-protein interactions.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Binding Sites / genetics
  • CHO Cells
  • Carbamates / chemistry
  • Carbamates / pharmacology
  • Cricetinae
  • Cricetulus
  • Humans
  • KCNQ Potassium Channels / genetics
  • KCNQ Potassium Channels / metabolism
  • KCNQ2 Potassium Channel / genetics
  • KCNQ2 Potassium Channel / metabolism*
  • KCNQ3 Potassium Channel / genetics
  • KCNQ3 Potassium Channel / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology
  • Membrane Transport Modulators / chemistry
  • Membrane Transport Modulators / pharmacology*
  • Molecular Sequence Data
  • Mutation
  • Phenylenediamines / chemistry
  • Phenylenediamines / pharmacology
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Sequence Alignment
  • Tryptophan / genetics
  • Tryptophan / metabolism


  • Anticonvulsants
  • Benzamides
  • Carbamates
  • KCNQ Potassium Channels
  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • KCNQ3 Potassium Channel
  • KCNQ3 protein, human
  • KCNQ5 protein, human
  • Membrane Transport Modulators
  • N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide
  • Phenylenediamines
  • Pyridines
  • ezogabine
  • Tryptophan