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Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7
Gain-of-function mutations in voltage-gated sodium channel Na(V)1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10083536/ https://www.ncbi.nlm.nih.gov/pubmed/36996107 http://dx.doi.org/10.1073/pnas.2219624120 |
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author | Wisedchaisri, Goragot Gamal El-Din, Tamer M. Zheng, Ning Catterall, William A. |
author_facet | Wisedchaisri, Goragot Gamal El-Din, Tamer M. Zheng, Ning Catterall, William A. |
author_sort | Wisedchaisri, Goragot |
collection | PubMed |
description | Gain-of-function mutations in voltage-gated sodium channel Na(V)1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: Na(V)1.7/I234T, Na(V)1.7/I848T, and Na(V)1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel Na(V)Ab recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the Na(V)1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of Na(V)1.7 and lead to severe pain in this debilitating disease. |
format | Online Article Text |
id | pubmed-10083536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-100835362023-09-30 Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 Wisedchaisri, Goragot Gamal El-Din, Tamer M. Zheng, Ning Catterall, William A. Proc Natl Acad Sci U S A Biological Sciences Gain-of-function mutations in voltage-gated sodium channel Na(V)1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: Na(V)1.7/I234T, Na(V)1.7/I848T, and Na(V)1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel Na(V)Ab recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the Na(V)1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of Na(V)1.7 and lead to severe pain in this debilitating disease. National Academy of Sciences 2023-03-30 2023-04-04 /pmc/articles/PMC10083536/ /pubmed/36996107 http://dx.doi.org/10.1073/pnas.2219624120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Wisedchaisri, Goragot Gamal El-Din, Tamer M. Zheng, Ning Catterall, William A. Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 |
title | Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 |
title_full | Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 |
title_fullStr | Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 |
title_full_unstemmed | Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 |
title_short | Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7 |
title_sort | structural basis for severe pain caused by mutations in the s4-s5 linkers of voltage-gated sodium channel na(v)1.7 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10083536/ https://www.ncbi.nlm.nih.gov/pubmed/36996107 http://dx.doi.org/10.1073/pnas.2219624120 |
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