BK channel inhibition by strong extracellular acidification

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Abstract

Mammalian BK-type voltage- and Ca²⁺-dependent K⁺ channels are found in a wide range of cells and intracellular organelles. Among different loci, the composition of the extracellular microenvironment, including pH, may differ substantially. For example, it has been reported that BK channels are expressed in lysosomes with their extracellular side facing the strongly acidified lysosomal lumen (pH ~ 4.5). Here we show that BK activation is strongly and reversibly inhibited by extracellular H⁺, with its conductance-voltage relationship shifted by more than +100 mV at pH_O 4. Our results reveal that this inhibition is mainly caused by H⁺ inhibition of BK voltage-sensor (VSD) activation through three acidic residues on the extracellular side of BK VSD. Given that these key residues (D133, D147, D153) are highly conserved among members in the voltage-dependent cation channel superfamily, the mechanism underlying BK inhibition by extracellular acidification might also be applicable to other members in the family.

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All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

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Yu Zhou

Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States

For correspondence
zhouy@wustl.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1623-7948
Xiaoming Xia

Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.
Christopher J Lingle

Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States

For correspondence
clingle@wustl.edu

Competing interests
The authors declare that no competing interests exist.

Funding

National Institute of General Medical Sciences (GM118114)

Christopher J Lingle

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20140150) of the Washington University School of Medicine. All surgery was performed under tricaine anesthesia, and every effort was made to minimize suffering.

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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.