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Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1

Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals. Their pore, formed by the assembly of three identical subunits, opens by an unknown mechanism. Here, to probe this mechanism, we investigate the interaction of Piezo1 with the...

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Autores principales: Lacroix, Jerome J., Botello-Smith, Wesley M., Luo, Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966384/
https://www.ncbi.nlm.nih.gov/pubmed/29795280
http://dx.doi.org/10.1038/s41467-018-04405-3
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author Lacroix, Jerome J.
Botello-Smith, Wesley M.
Luo, Yun
author_facet Lacroix, Jerome J.
Botello-Smith, Wesley M.
Luo, Yun
author_sort Lacroix, Jerome J.
collection PubMed
description Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals. Their pore, formed by the assembly of three identical subunits, opens by an unknown mechanism. Here, to probe this mechanism, we investigate the interaction of Piezo1 with the small molecule agonist Yoda1. By engineering chimeras between mouse Piezo1 and its Yoda1-insensitive paralog Piezo2, we first identify a minimal protein region required for Yoda1 sensitivity. We next study the effect of Yoda1 on heterotrimeric Piezo1 channels harboring wild type subunits and Yoda1-insensitive mutant subunits. Using calcium imaging and patch-clamp electrophysiology, we show that hybrid channels harboring as few as one Yoda1-sensitive subunit exhibit Yoda1 sensitivity undistinguishable from homotrimeric wild type channels. Our results show that the Piezo1 pore remains fully open if only one subunit remains activated. This study sheds light on the gating and pharmacological mechanisms of a member of the Piezo channel family.
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spelling pubmed-59663842018-05-25 Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1 Lacroix, Jerome J. Botello-Smith, Wesley M. Luo, Yun Nat Commun Article Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals. Their pore, formed by the assembly of three identical subunits, opens by an unknown mechanism. Here, to probe this mechanism, we investigate the interaction of Piezo1 with the small molecule agonist Yoda1. By engineering chimeras between mouse Piezo1 and its Yoda1-insensitive paralog Piezo2, we first identify a minimal protein region required for Yoda1 sensitivity. We next study the effect of Yoda1 on heterotrimeric Piezo1 channels harboring wild type subunits and Yoda1-insensitive mutant subunits. Using calcium imaging and patch-clamp electrophysiology, we show that hybrid channels harboring as few as one Yoda1-sensitive subunit exhibit Yoda1 sensitivity undistinguishable from homotrimeric wild type channels. Our results show that the Piezo1 pore remains fully open if only one subunit remains activated. This study sheds light on the gating and pharmacological mechanisms of a member of the Piezo channel family. Nature Publishing Group UK 2018-05-23 /pmc/articles/PMC5966384/ /pubmed/29795280 http://dx.doi.org/10.1038/s41467-018-04405-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lacroix, Jerome J.
Botello-Smith, Wesley M.
Luo, Yun
Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
title Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
title_full Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
title_fullStr Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
title_full_unstemmed Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
title_short Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
title_sort probing the gating mechanism of the mechanosensitive channel piezo1 with the small molecule yoda1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966384/
https://www.ncbi.nlm.nih.gov/pubmed/29795280
http://dx.doi.org/10.1038/s41467-018-04405-3
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