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Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy

Akira Uehara1, Yuki Nakamura, Takao Shioya

  • 1Department of Physiology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. ueharaak@fukuoka-u.ac.jp

The Journal of Membrane Biology
|April 22, 2008
PubMed

Insights

A mutation in KCNQ3 potassium channels (W309R) disrupts channel function, potentially causing epilepsy. This study reveals the critical role of specific residues in maintaining normal potassium channel activity and structure.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Biophysics

Background:

  • The WW motif in K+ channels is crucial for function.
  • Tryptophan (W) and tyrosine (Y) residues in pore helices and selectivity filters are key interaction sites.
  • A W309R mutation in KCNQ3 subunits affects M-channels.

Purpose of the Study:

  • To investigate the functional impact of the W309R mutation in KCNQ channels.
  • To understand the structural and functional consequences of altered pore helix-selectivity filter interactions.

Main Methods:

  • Heterologous expression of KCNQ channel variants (KCNQ3W309R, KCNQ2/KCNQ3W309R).
  • Electrophysiological recordings to assess KCNQ currents and gating properties.
  • Three-dimensional homology modeling to analyze structural changes.

Main Results:

  • Homomeric KCNQ3W309R channels showed no KCNQ currents.
  • Heteromeric KCNQ2/KCNQ3W309R channels exhibited dominant-negative current suppression and altered gating.
  • Homology modeling suggested the R side chain is too distant from the Y side chain for stabilizing interactions.

Conclusions:

  • The interaction between pore helix W residues and selectivity filter Y residues is essential for K+ channel function.
  • The W309R mutation impairs K+ channel function, potentially leading to channel dysfunction and epileptic hyperexcitability in the brain.

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