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Altered KCNQ3 Potassium Channel Function Caused by the W309R Pore-Helix Mutation Found in Human Epilepsy

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Abstract

The second tryptophan (W) residue of the conserved WW motif in the pore helix of many K+ channel subunit is thought to interact with the tyrosine (Y) residues of the selectivity filter. A missense mutation causing the replacement of the corresponding residues with an arginine (W309R) occurs in KCNQ3 subunits forming part of M-channels. In this study, we examined the functional consequences of the W309R mutation in heterogously expressed KCNQ channels. Homomeric KCNQ3W309R channels lacked KCNQ currents. Heteromeric KCNQ2/KCNQ3W309R channels displayed a dominant-negative suppression of current and a significant modification in gating properties when compared with heteromeric KCNQ3/KCNQ2 channels mimicking the M-channels. A three-dimensional homology model in the W309R mutant indicated that the R side chain of pore helices is too far from the Y side chain of the selectivity filter to interact via hydrogen bonds with each other and stabilize the pore structure. Collectively, the present results suggest that the second W residues of pore helices and their chemical interaction with the Y residues of the selectivity filter are essential for normal K+ channel function. This pore-helix mutation, if occurs in the brain M channels, could thus lead to a channel dysfunction sufficient to trigger epileptic hyperexcitability.

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Acknowledgements

The authors thank A. Hamachi and M. Yonetani for technical assistance and Drs. S. Matsuoka, T. Ishii and N. Aoki for valuable comments. This work was supported by a Grant-in Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Akira Uehara & Yuki Nakamura

  2. Department of Physiology, School of Medicine, Saga University, 1-1, 5-chome, Nabeshima, Saga, 849-8501, Japan

    Takao Shioya

  3. Department of Pediatrics, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Shinichi Hirose

  4. Laboratory of Human Biology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Midori Yasukochi

  5. Department of Cell Biology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Kiyoko Uehara

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  1. Akira Uehara
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  2. Yuki Nakamura
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  3. Takao Shioya
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  4. Shinichi Hirose
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  5. Midori Yasukochi
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  6. Kiyoko Uehara
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Correspondence to Akira Uehara.

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Uehara, A., Nakamura, Y., Shioya, T. et al. Altered KCNQ3 Potassium Channel Function Caused by the W309R Pore-Helix Mutation Found in Human Epilepsy. J Membrane Biol 222, 55–63 (2008). https://doi.org/10.1007/s00232-008-9097-5

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