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µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7
µ-Conotoxins are small, potent, peptide voltage-gated sodium (Na(V)) channel inhibitors characterised by a conserved cysteine framework. Despite promising in vivo studies indicating analgesic potential of these compounds, selectivity towards the therapeutically relevant subtype Na(V)1.7 has so far b...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506549/ https://www.ncbi.nlm.nih.gov/pubmed/36136538 http://dx.doi.org/10.3390/toxins14090600 |
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author | McMahon, Kirsten L. Tran, Hue N. T. Deuis, Jennifer R. Craik, David J. Vetter, Irina Schroeder, Christina I. |
author_facet | McMahon, Kirsten L. Tran, Hue N. T. Deuis, Jennifer R. Craik, David J. Vetter, Irina Schroeder, Christina I. |
author_sort | McMahon, Kirsten L. |
collection | PubMed |
description | µ-Conotoxins are small, potent, peptide voltage-gated sodium (Na(V)) channel inhibitors characterised by a conserved cysteine framework. Despite promising in vivo studies indicating analgesic potential of these compounds, selectivity towards the therapeutically relevant subtype Na(V)1.7 has so far been limited. We recently identified a novel µ-conotoxin, SxIIIC, which potently inhibits human Na(V)1.7 (hNa(V)1.7). SxIIIC has high sequence homology with other µ-conotoxins, including SmIIIA and KIIIA, yet shows different Na(V) channel selectivity for mammalian subtypes. Here, we evaluated and compared the inhibitory potency of µ-conotoxins SxIIIC, SmIIIA and KIIIA at hNa(V) channels by whole-cell patch-clamp electrophysiology and discovered that these three closely related µ-conotoxins display unique selectivity profiles with significant variations in inhibitory potency at hNa(V)1.7. Analysis of other µ-conotoxins at hNa(V)1.7 shows that only a limited number are capable of inhibition at this subtype and that differences between the number of residues in loop 3 appear to influence the ability of µ-conotoxins to inhibit hNa(V)1.7. Through mutagenesis studies, we confirmed that charged residues in this region also affect the selectivity for hNa(V)1.4. Comparison of µ-conotoxin NMR solution structures identified differences that may contribute to the variance in hNa(V)1.7 inhibition and validated the role of the loop 1 extension in SxIIIC for improving potency at hNa(V)1.7, when compared to KIIIA. This work could assist in designing µ-conotoxin derivatives specific for hNa(V)1.7. |
format | Online Article Text |
id | pubmed-9506549 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95065492022-09-24 µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 McMahon, Kirsten L. Tran, Hue N. T. Deuis, Jennifer R. Craik, David J. Vetter, Irina Schroeder, Christina I. Toxins (Basel) Article µ-Conotoxins are small, potent, peptide voltage-gated sodium (Na(V)) channel inhibitors characterised by a conserved cysteine framework. Despite promising in vivo studies indicating analgesic potential of these compounds, selectivity towards the therapeutically relevant subtype Na(V)1.7 has so far been limited. We recently identified a novel µ-conotoxin, SxIIIC, which potently inhibits human Na(V)1.7 (hNa(V)1.7). SxIIIC has high sequence homology with other µ-conotoxins, including SmIIIA and KIIIA, yet shows different Na(V) channel selectivity for mammalian subtypes. Here, we evaluated and compared the inhibitory potency of µ-conotoxins SxIIIC, SmIIIA and KIIIA at hNa(V) channels by whole-cell patch-clamp electrophysiology and discovered that these three closely related µ-conotoxins display unique selectivity profiles with significant variations in inhibitory potency at hNa(V)1.7. Analysis of other µ-conotoxins at hNa(V)1.7 shows that only a limited number are capable of inhibition at this subtype and that differences between the number of residues in loop 3 appear to influence the ability of µ-conotoxins to inhibit hNa(V)1.7. Through mutagenesis studies, we confirmed that charged residues in this region also affect the selectivity for hNa(V)1.4. Comparison of µ-conotoxin NMR solution structures identified differences that may contribute to the variance in hNa(V)1.7 inhibition and validated the role of the loop 1 extension in SxIIIC for improving potency at hNa(V)1.7, when compared to KIIIA. This work could assist in designing µ-conotoxin derivatives specific for hNa(V)1.7. MDPI 2022-08-30 /pmc/articles/PMC9506549/ /pubmed/36136538 http://dx.doi.org/10.3390/toxins14090600 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article McMahon, Kirsten L. Tran, Hue N. T. Deuis, Jennifer R. Craik, David J. Vetter, Irina Schroeder, Christina I. µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 |
title | µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 |
title_full | µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 |
title_fullStr | µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 |
title_full_unstemmed | µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 |
title_short | µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na(V)1.7 |
title_sort | µ-conotoxins targeting the human voltage-gated sodium channel subtype na(v)1.7 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506549/ https://www.ncbi.nlm.nih.gov/pubmed/36136538 http://dx.doi.org/10.3390/toxins14090600 |
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