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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2020-09-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.134174 |
| _version_ | 1818643600390488064 |
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| author | Benjamin Gaston Laura Smith Jürgen Bosch James Seckler Diana Kunze Janna Kiselar Nadzeya Marozkina Craig A. Hodges Patrick Wintrobe Kellen McGee Tatiana S. Morozkina Spencer T. Burton Tristan Lewis Timothy Strassmaier Paulina Getsy James N. Bates Stephen J. Lewis |
| author_facet | Benjamin Gaston Laura Smith Jürgen Bosch James Seckler Diana Kunze Janna Kiselar Nadzeya Marozkina Craig A. Hodges Patrick Wintrobe Kellen McGee Tatiana S. Morozkina Spencer T. Burton Tristan Lewis Timothy Strassmaier Paulina Getsy James N. Bates Stephen J. Lewis |
| author_sort | Benjamin Gaston |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T00:01:32Z |
| format | Article |
| id | doaj.art-0d6ea0f326f84f139e9fc944a5002b14 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-17T00:01:32Z |
| publishDate | 2020-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0d6ea0f326f84f139e9fc944a5002b142022-12-21T22:11:03ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-09-01518Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signalingBenjamin GastonLaura SmithJürgen BoschJames SecklerDiana KunzeJanna KiselarNadzeya MarozkinaCraig A. HodgesPatrick WintrobeKellen McGeeTatiana S. MorozkinaSpencer T. BurtonTristan LewisTimothy StrassmaierPaulina GetsyJames N. BatesStephen J. LewisS-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.https://doi.org/10.1172/jci.insight.134174Cell biology |
| spellingShingle | Benjamin Gaston Laura Smith Jürgen Bosch James Seckler Diana Kunze Janna Kiselar Nadzeya Marozkina Craig A. Hodges Patrick Wintrobe Kellen McGee Tatiana S. Morozkina Spencer T. Burton Tristan Lewis Timothy Strassmaier Paulina Getsy James N. Bates Stephen J. Lewis Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling JCI Insight Cell biology |
| 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 | Cell biology |
| url | https://doi.org/10.1172/jci.insight.134174 |
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