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Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors

Author

Listed:
  • Ming Zhou

    (Howard Hughes Medical Institute, Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University)

  • João H. Morais-Cabral

    (Howard Hughes Medical Institute, Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University
    Yale University)

  • Sabine Mann

    (Howard Hughes Medical Institute, Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University)

  • Roderick MacKinnon

    (Howard Hughes Medical Institute, Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University)

Abstract

Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity and inner pore of the K+ channel form the receptor site for both the inactivation gate and small-molecule inhibitors. We propose that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of K+ channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.

Suggested Citation

  • Ming Zhou & João H. Morais-Cabral & Sabine Mann & Roderick MacKinnon, 2001. "Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors," Nature, Nature, vol. 411(6838), pages 657-661, June.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6838:d:10.1038_35079500
    DOI: 10.1038/35079500
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    Cited by:

    1. Jiangtao Zhang & Yiqiang Shi & Junping Fan & Huiwen Chen & Zhanyi Xia & Bo Huang & Juquan Jiang & Jianke Gong & Zhuo Huang & Daohua Jiang, 2022. "N-type fast inactivation of a eukaryotic voltage-gated sodium channel," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Paul J Pfaffinger, 2013. "A Conserved Pre-Block Interaction Motif Regulates Potassium Channel Activation and N-Type Inactivation," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-14, November.
    3. Matthew R Skerritt & Donald L Campbell, 2008. "Non-Native R1 Substitution in the S4 Domain Uniquely Alters Kv4.3 Channel Gating," PLOS ONE, Public Library of Science, vol. 3(11), pages 1-7, November.

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