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BK channel inhibition by strong extracellular acidification

Mammalian BK-type voltage- and Ca(2+)-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 e...

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Detalles Bibliográficos
Autores principales: Zhou, Yu, Xia, Xiao-Ming, Lingle, Christopher J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054526/
https://www.ncbi.nlm.nih.gov/pubmed/29963986
http://dx.doi.org/10.7554/eLife.38060
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author Zhou, Yu
Xia, Xiao-Ming
Lingle, Christopher J
author_facet Zhou, Yu
Xia, Xiao-Ming
Lingle, Christopher J
author_sort Zhou, Yu
collection PubMed
description Mammalian BK-type voltage- and Ca(2+)-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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spelling pubmed-60545262018-07-23 BK channel inhibition by strong extracellular acidification Zhou, Yu Xia, Xiao-Ming Lingle, Christopher J eLife Structural Biology and Molecular Biophysics Mammalian BK-type voltage- and Ca(2+)-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. eLife Sciences Publications, Ltd 2018-07-02 /pmc/articles/PMC6054526/ /pubmed/29963986 http://dx.doi.org/10.7554/eLife.38060 Text en © 2018, Zhou et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Zhou, Yu
Xia, Xiao-Ming
Lingle, Christopher J
BK channel inhibition by strong extracellular acidification
title BK channel inhibition by strong extracellular acidification
title_full BK channel inhibition by strong extracellular acidification
title_fullStr BK channel inhibition by strong extracellular acidification
title_full_unstemmed BK channel inhibition by strong extracellular acidification
title_short BK channel inhibition by strong extracellular acidification
title_sort bk channel inhibition by strong extracellular acidification
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054526/
https://www.ncbi.nlm.nih.gov/pubmed/29963986
http://dx.doi.org/10.7554/eLife.38060
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AT linglechristopherj bkchannelinhibitionbystrongextracellularacidification