Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants

Nat Chem Biol. 2007 May;3(5):287-96. doi: 10.1038/nchembio874. Epub 2007 Apr 15.


KCNQ potassium channels are activated by changes in transmembrane voltage and play an important role in controlling electrical excitability. Human mutations of KCNQ2 and KCNQ3 potassium channel genes result in reduction or loss of channel activity and cause benign familial neonatal convulsions (BFNCs). Thus, small molecules capable of augmenting KCNQ currents are essential both for understanding the mechanism of channel activity and for developing therapeutics. We performed a high-throughput screen in search for agonistic compounds potentiating KCNQ potassium channels. Here we report identification of a new opener, zinc pyrithione (1), which activates both recombinant and native KCNQ M currents. Interactions with the channel protein cause an increase of single-channel open probability that could fully account for the overall conductance increase. Separate point mutations have been identified that either shift the concentration dependence or affect potentiation efficacy, thereby providing evidence for residues influencing ligand binding and downstream events. Furthermore, zinc pyrithione is capable of rescuing the mutant channels causal to BFNCs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Electrophysiology
  • Epilepsy / genetics*
  • Epilepsy / metabolism*
  • Humans
  • Ion Channel Gating / drug effects*
  • KCNQ Potassium Channels / chemistry
  • KCNQ Potassium Channels / genetics
  • KCNQ Potassium Channels / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Mutation / genetics*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • Patch-Clamp Techniques
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Sensitivity and Specificity


  • KCNQ Potassium Channels
  • Organometallic Compounds
  • Pyridines
  • pyrithione zinc

Associated data

  • PDB/2A79
  • PubChem-Substance/24263037
  • PubChem-Substance/24263038
  • PubChem-Substance/24263039
  • PubChem-Substance/24263040
  • PubChem-Substance/24263041
  • PubChem-Substance/24263042
  • PubChem-Substance/24263043
  • PubChem-Substance/24263044
  • PubChem-Substance/24263045
  • PubChem-Substance/24263046