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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 294/6/C1476    most recent 00479.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Labro, A. J. Articles by Snyders, D. J. Search for Related Content PubMed PubMed Citation Articles by Labro, A. J. Articles by Snyders, D. J.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

A Kv channel with an altered activation gate sequence displays both "fast" and "slow" activation kinetics

¹Laboratory for Molecular Biophysics, Physiology, and Pharmacology, Department of Biomedical Sciences, University of Antwerp, Belgium; and ²Laboratory for Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Submitted 11 October 2007 ; accepted in final form 26 March 2008

The Kv1–4 families of K⁺ channels contain a tandem proline motif (PXP) in the S6 helix that is crucial for channel gating. In human Kv1.5, replacing the first proline by an alanine resulted in a nonfunctional channel. This mutant was rescued by introducing another proline at a nearby position, changing the sequence into AVPP. This resulted in a channel that activated quickly (ms range) upon the first depolarization. However, thereafter, the channel became trapped in another gating mode that was characterized by slow activation kinetics (s range) with a shallow voltage dependence. The switch in gating mode was observed even with very short depolarization steps, but recovery to the initial "fast" mode was extremely slow. Computational modeling suggested that switching occurred during channel deactivation. To test the effect of the altered PXP sequence on the mobility of the S6 helix, we used molecular dynamics simulations of the isolated S6 domain of wild type (WT) and mutants starting from either a closed or open conformation. The WT S6 helix displayed movements around the PXP region with simulations starting from either state. However, the S6 with a AVPP sequence displayed flexibility only when started from the closed conformation and was rigid when started from the open state. These results indicate that the region around the PXP motif may serve as a "hinge" and that changing the sequence to AVPP results in channels that deactivate to a state with an alternate configuration that renders them "reluctant" to open subsequently.

voltage-gated potassium channel