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Originally published as Biophys J. BioFAST on August 17, 2007.
doi:10.1529/biophysj.107.107987
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Biophysical Journal 93:4159-4172 (2007)
© 2007 The Biophysical Society

An Inactivation Gate in the Selectivity Filter of KCNQ1 Potassium Channels

Gilad Gibor *, Daniel Yakubovich *, Avia Rosenhouse-Dantsker {dagger}, Asher Peretz *, Hella Schottelndreier *, Guiscard Seebohm {ddagger}, Nathan Dascal *, Diomedes E. Logothetis {dagger}, Yoav Paas § and Bernard Attali *

* Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel; {dagger} Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York; {ddagger} Physiologisches Institut I, Universität Tübingen, Tübingen, Germany; and § The Mina and Everard Goodman Faculty of Life Sciences Bar-Ilan University, Ramat-Gan, Israel

Correspondence: Address reprint requests to Bernard Attali, PhD, Tel.: 972-3640-5116; E-mail: battali{at}post.tau.ac.il; or Yoav Paas, PhD, Tel.: 973-3531-7968; E-mail: paasyo{at}mail.biu.ac.il.

Inactivation is an inherent property of most voltage-gated K+ channels. While fast N-type inactivation has been analyzed in biophysical and structural details, the mechanisms underlying slow inactivation are yet poorly understood. Here, we characterized a slow inactivation mechanism in various KCNQ1 pore mutants, including L273F, which hinders entry of external Ba2+ to its deep site in the pore and traps it by slowing its egress. Kinetic studies, molecular modeling, and dynamics simulations suggest that this slow inactivation involves conformational changes that converge to the outer carbonyl ring of the selectivity filter, where the backbone becomes less flexible. This mechanism involves acceleration of inactivation kinetics and enhancement of Ba2+ trapping at elevated external K+ concentrations. Hence, KCNQ1 slow inactivation considerably differs from C-type inactivation where vacation of K+ from the filter was invoked. We suggest that trapping of K+ at s1 due to filter rigidity and hindrance of the dehydration-resolvation transition underlie the slow inactivation of KCNQ1 pore mutants.




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Copyright © 2007 by the Biophysical Society.