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A Molecular Switch Driving Inactivation in the Cardiac K+ Channel hERG

Author

Listed:
  • David A Köpfer
  • Ulrike Hahn
  • Iris Ohmert
  • Gert Vriend
  • Olaf Pongs
  • Bert L de Groot
  • Ulrich Zachariae

Abstract

K+ channels control transmembrane action potentials by gating open or closed in response to external stimuli. Inactivation gating, involving a conformational change at the K+ selectivity filter, has recently been recognized as a major K+ channel regulatory mechanism. In the K+ channel hERG, inactivation controls the length of the human cardiac action potential. Mutations impairing hERG inactivation cause life-threatening cardiac arrhythmia, which also occur as undesired side effects of drugs. In this paper, we report atomistic molecular dynamics simulations, complemented by mutational and electrophysiological studies, which suggest that the selectivity filter adopts a collapsed conformation in the inactivated state of hERG. The selectivity filter is gated by an intricate hydrogen bond network around residues S620 and N629. Mutations of this hydrogen bond network are shown to cause inactivation deficiency in electrophysiological measurements. In addition, drug-related conformational changes around the central cavity and pore helix provide a functional mechanism for newly discovered hERG activators.

Suggested Citation

  • David A Köpfer & Ulrike Hahn & Iris Ohmert & Gert Vriend & Olaf Pongs & Bert L de Groot & Ulrich Zachariae, 2012. "A Molecular Switch Driving Inactivation in the Cardiac K+ Channel hERG," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-11, July.
    • Handle: RePEc:plo:pone00:0041023
    DOI: 10.1371/journal.pone.0041023
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    References listed on IDEAS

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    2. Luis G. Cuello & Vishwanath Jogini & D. Marien Cortes & Eduardo Perozo, 2010. "Structural mechanism of C-type inactivation in K+ channels," Nature, Nature, vol. 466(7303), pages 203-208, July.
    3. Yufeng Zhou & João H. Morais-Cabral & Amelia Kaufman & Roderick MacKinnon, 2001. "Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution," Nature, Nature, vol. 414(6859), pages 43-48, November.
    4. Michael C. Sanguinetti & Martin Tristani-Firouzi, 2006. "hERG potassium channels and cardiac arrhythmia," Nature, Nature, vol. 440(7083), pages 463-469, March.
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