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Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms
Voltage-gated Na(+) (Na(V)) channels regulate homeostasis in bacteria and control membrane electrical excitability in mammals. Compared to their mammalian counterparts, bacterial Na(V) channels possess a simpler, fourfold symmetric structure and have facilitated studies of the structural basis of ch...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329812/ https://www.ncbi.nlm.nih.gov/pubmed/32612253 http://dx.doi.org/10.1038/s41598-020-67761-5 |
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author | Zhu, Wandi Li, Tianbo Silva, Jonathan R. Chen, Jun |
author_facet | Zhu, Wandi Li, Tianbo Silva, Jonathan R. Chen, Jun |
author_sort | Zhu, Wandi |
collection | PubMed |
description | Voltage-gated Na(+) (Na(V)) channels regulate homeostasis in bacteria and control membrane electrical excitability in mammals. Compared to their mammalian counterparts, bacterial Na(V) channels possess a simpler, fourfold symmetric structure and have facilitated studies of the structural basis of channel gating. However, the pharmacology of bacterial Na(V) remains largely unexplored. Here we systematically screened 39 Na(V) modulators on a bacterial channel (NaChBac) and characterized a selection of compounds on NaChBac and a mammalian channel (human Na(V)1.7). We found that while many compounds interact with both channels, they exhibit distinct functional effects. For example, the local anesthetics ambroxol and lidocaine block both Na(V)1.7 and NaChBac but affect activation and inactivation of the two channels to different extents. The voltage-sensing domain targeting toxin BDS-I increases Na(V)1.7 but decreases NaChBac peak currents. The pore binding toxins aconitine and veratridine block peak currents of Na(V)1.7 and shift activation (aconitine) and inactivation (veratridine) respectively. In NaChBac, they block the peak current by binding to the pore residue F224. Nonetheless, aconitine has no effect on activation or inactivation, while veratridine only modulates activation of NaChBac. The conservation and divergence in the pharmacology of bacterial and mammalian Na(V) channels provide insights into the molecular basis of channel gating and will facilitate organism-specific drug discovery. |
format | Online Article Text |
id | pubmed-7329812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73298122020-07-06 Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms Zhu, Wandi Li, Tianbo Silva, Jonathan R. Chen, Jun Sci Rep Article Voltage-gated Na(+) (Na(V)) channels regulate homeostasis in bacteria and control membrane electrical excitability in mammals. Compared to their mammalian counterparts, bacterial Na(V) channels possess a simpler, fourfold symmetric structure and have facilitated studies of the structural basis of channel gating. However, the pharmacology of bacterial Na(V) remains largely unexplored. Here we systematically screened 39 Na(V) modulators on a bacterial channel (NaChBac) and characterized a selection of compounds on NaChBac and a mammalian channel (human Na(V)1.7). We found that while many compounds interact with both channels, they exhibit distinct functional effects. For example, the local anesthetics ambroxol and lidocaine block both Na(V)1.7 and NaChBac but affect activation and inactivation of the two channels to different extents. The voltage-sensing domain targeting toxin BDS-I increases Na(V)1.7 but decreases NaChBac peak currents. The pore binding toxins aconitine and veratridine block peak currents of Na(V)1.7 and shift activation (aconitine) and inactivation (veratridine) respectively. In NaChBac, they block the peak current by binding to the pore residue F224. Nonetheless, aconitine has no effect on activation or inactivation, while veratridine only modulates activation of NaChBac. The conservation and divergence in the pharmacology of bacterial and mammalian Na(V) channels provide insights into the molecular basis of channel gating and will facilitate organism-specific drug discovery. Nature Publishing Group UK 2020-07-01 /pmc/articles/PMC7329812/ /pubmed/32612253 http://dx.doi.org/10.1038/s41598-020-67761-5 Text en © The Author(s) 2020 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 Zhu, Wandi Li, Tianbo Silva, Jonathan R. Chen, Jun Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms |
title | Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms |
title_full | Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms |
title_fullStr | Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms |
title_full_unstemmed | Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms |
title_short | Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms |
title_sort | conservation and divergence in nachbac and na(v)1.7 pharmacology reveals novel drug interaction mechanisms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329812/ https://www.ncbi.nlm.nih.gov/pubmed/32612253 http://dx.doi.org/10.1038/s41598-020-67761-5 |
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