AN INACTIVATION GATE IN THE SELECTIVITY FILTER OF KCNQ1 POTASSIUM CHANNELS

¹ Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University
² Department of Physiology and Biophysics, Mount Sinai School of Medicine
³ Physiologisches Institut I, Universität Tübingen
⁴ Faculty of Life Sciences Bar-Ilan University
⁵ Dept of Physiology & Pharmacology

^* To whom correspondence should be addressed. E-mail: battali{at}post.tau.ac.il.

Submitted on March 2, 2007
Revised on March 23, 2007
Accepted on 17 July 2007

	Abstract

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.

Key Words: Kv7, gating, ion channel, permeation, pore, selectivity filter

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