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Deacetylation as a receptor-regulated direct activation switch for pannexin channels
Activation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel ope...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302610/ https://www.ncbi.nlm.nih.gov/pubmed/34301959 http://dx.doi.org/10.1038/s41467-021-24825-y |
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author | Chiu, Yu-Hsin Medina, Christopher B. Doyle, Catherine A. Zhou, Ming Narahari, Adishesh K. Sandilos, Joanna K. Gonye, Elizabeth C. Gao, Hong-Yu Guo, Shih Yi Parlak, Mahmut Lorenz, Ulrike M. Conrads, Thomas P. Desai, Bimal N. Ravichandran, Kodi S. Bayliss, Douglas A. |
author_facet | Chiu, Yu-Hsin Medina, Christopher B. Doyle, Catherine A. Zhou, Ming Narahari, Adishesh K. Sandilos, Joanna K. Gonye, Elizabeth C. Gao, Hong-Yu Guo, Shih Yi Parlak, Mahmut Lorenz, Ulrike M. Conrads, Thomas P. Desai, Bimal N. Ravichandran, Kodi S. Bayliss, Douglas A. |
author_sort | Chiu, Yu-Hsin |
collection | PubMed |
description | Activation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia – histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism. |
format | Online Article Text |
id | pubmed-8302610 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-83026102021-08-12 Deacetylation as a receptor-regulated direct activation switch for pannexin channels Chiu, Yu-Hsin Medina, Christopher B. Doyle, Catherine A. Zhou, Ming Narahari, Adishesh K. Sandilos, Joanna K. Gonye, Elizabeth C. Gao, Hong-Yu Guo, Shih Yi Parlak, Mahmut Lorenz, Ulrike M. Conrads, Thomas P. Desai, Bimal N. Ravichandran, Kodi S. Bayliss, Douglas A. Nat Commun Article Activation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia – histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism. Nature Publishing Group UK 2021-07-23 /pmc/articles/PMC8302610/ /pubmed/34301959 http://dx.doi.org/10.1038/s41467-021-24825-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chiu, Yu-Hsin Medina, Christopher B. Doyle, Catherine A. Zhou, Ming Narahari, Adishesh K. Sandilos, Joanna K. Gonye, Elizabeth C. Gao, Hong-Yu Guo, Shih Yi Parlak, Mahmut Lorenz, Ulrike M. Conrads, Thomas P. Desai, Bimal N. Ravichandran, Kodi S. Bayliss, Douglas A. Deacetylation as a receptor-regulated direct activation switch for pannexin channels |
title | Deacetylation as a receptor-regulated direct activation switch for pannexin channels |
title_full | Deacetylation as a receptor-regulated direct activation switch for pannexin channels |
title_fullStr | Deacetylation as a receptor-regulated direct activation switch for pannexin channels |
title_full_unstemmed | Deacetylation as a receptor-regulated direct activation switch for pannexin channels |
title_short | Deacetylation as a receptor-regulated direct activation switch for pannexin channels |
title_sort | deacetylation as a receptor-regulated direct activation switch for pannexin channels |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302610/ https://www.ncbi.nlm.nih.gov/pubmed/34301959 http://dx.doi.org/10.1038/s41467-021-24825-y |
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