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Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling
S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase–independent (sGC-independent) effects are stereoselective — that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) — and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identi...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526540/ https://www.ncbi.nlm.nih.gov/pubmed/32790645 http://dx.doi.org/10.1172/jci.insight.134174 |
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author | Gaston, Benjamin Smith, Laura Bosch, Jürgen Seckler, James Kunze, Diana Kiselar, Janna Marozkina, Nadzeya Hodges, Craig A. Wintrobe, Patrick McGee, Kellen Morozkina, Tatiana S. Burton, Spencer T. Lewis, Tristan Strassmaier, Timothy Getsy, Paulina Bates, James N. Lewis, Stephen J. |
author_facet | Gaston, Benjamin Smith, Laura Bosch, Jürgen Seckler, James Kunze, Diana Kiselar, Janna Marozkina, Nadzeya Hodges, Craig A. Wintrobe, Patrick McGee, Kellen Morozkina, Tatiana S. Burton, Spencer T. Lewis, Tristan Strassmaier, Timothy Getsy, Paulina Bates, James N. Lewis, Stephen J. |
author_sort | Gaston, Benjamin |
collection | PubMed |
description | S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase–independent (sGC-independent) effects are stereoselective — that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) — and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays — followed by unbiased proteomic analysis — to identify voltage-gated K(+) channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO–Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvβ2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance. |
format | Online Article Text |
id | pubmed-7526540 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-75265402020-10-05 Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling Gaston, Benjamin Smith, Laura Bosch, Jürgen Seckler, James Kunze, Diana Kiselar, Janna Marozkina, Nadzeya Hodges, Craig A. Wintrobe, Patrick McGee, Kellen Morozkina, Tatiana S. Burton, Spencer T. Lewis, Tristan Strassmaier, Timothy Getsy, Paulina Bates, James N. Lewis, Stephen J. JCI Insight Research Article S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase–independent (sGC-independent) effects are stereoselective — that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) — and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays — followed by unbiased proteomic analysis — to identify voltage-gated K(+) channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO–Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvβ2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance. American Society for Clinical Investigation 2020-09-17 /pmc/articles/PMC7526540/ /pubmed/32790645 http://dx.doi.org/10.1172/jci.insight.134174 Text en © 2020 Gaston et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Gaston, Benjamin Smith, Laura Bosch, Jürgen Seckler, James Kunze, Diana Kiselar, Janna Marozkina, Nadzeya Hodges, Craig A. Wintrobe, Patrick McGee, Kellen Morozkina, Tatiana S. Burton, Spencer T. Lewis, Tristan Strassmaier, Timothy Getsy, Paulina Bates, James N. Lewis, Stephen J. Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling |
title | Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling |
title_full | Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling |
title_fullStr | Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling |
title_full_unstemmed | Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling |
title_short | Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling |
title_sort | voltage-gated potassium channel proteins and stereoselective s-nitroso-l-cysteine signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526540/ https://www.ncbi.nlm.nih.gov/pubmed/32790645 http://dx.doi.org/10.1172/jci.insight.134174 |
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