Mechanism of activation at the selectivity filter of the KcsA K+ channel

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Abstract

Potassium channels are opened by ligands and/or membrane potential. In voltage-gated K⁺ channels and the prokaryotic KcsA channel, conduction is believed to result from opening of an intracellular constriction that prevents ion entry into the pore. On the other hand, numerous ligand-gated K⁺ channels lack such gate, suggesting that they may be activated by a change within the selectivity filter, a narrow region at the extracellular side of the pore. Using molecular dynamics simulations and electrophysiology measurements, we show that ligand-induced conformational changes in the KcsA channel removes steric restraints at the selectivity filter, thus resulting in structural fluctuations, reduced K⁺ affinity, and increased ion permeation. Such activation of the selectivity filter may be a universal gating mechanism within K⁺ channels. The occlusion of the pore at the level of the intracellular gate appears to be secondary.

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Florian T Heer

SIB Swiss Institute of Bioinformatics, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.
David J Posson

Department of Anesthesiology, Weill Cornell Medical College, New York, United States

Competing interests
The authors declare that no competing interests exist.
Wojciech Wojtas-Niziurski

SIB Swiss Institute of Bioinformatics, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.
Crina M Nimigean

Department of Anesthesiology, Weill Cornell Medical College, New York, United States

For correspondence
crn2002@med.cornell.edu

Competing interests
The authors declare that no competing interests exist.
Simon Bernèche

SIB Swiss Institute of Bioinformatics, Basel, Switzerland

For correspondence
simon.berneche@unibas.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6274-4094

Funding

Swiss National Science Foundation (SNF Professorship No PP00P3_139205)

Simon Bernèche

FP7 European Union (Human Brain Project No 604102)

Simon Bernèche

NIH Office of the Director (R01GM088352)

Crina M Nimigean

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.