Journal article
Voltage-gated potassium channel proteins and stereoselective S-nitroso-L-cysteine signaling
JCI insight, Vol.5(18), e134174
09/17/2020
DOI: 10.1172/jci.insight.134174
PMCID: PMC7526540
PMID: 32790645
Abstract
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-o-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 proteornic 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 plasrnon resonance spectroscopy; hydrogen deuterium exchange; and, in 101.1/Kv1.2/K beta 2-overexpressing cells, patch clamp assays. Remarkably, these sGCindependent 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.
Details
- Title: Subtitle
- Voltage-gated potassium channel proteins and stereoselective S-nitroso-L-cysteine signaling
- Creators
- Benjamin Gaston - Indiana UniversityLaura Smith - Case Western Reserve UniversityJurgen Bosch - Case Western Reserve Univ, Dept Pediat Pulmonol, Cleveland, OH 44106 USAJames Seckler - Case Western Reserve UniversityDiana Kunze - Case Western Reserve UniversityJanna Kiselar - Case Western Reserve UniversityNadzeya Marozkina - Case Western Reserve UniversityCraig A. Hodges - Case Western Reserve UniversityPatrick Wintrobe - Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USAKellen McGee - Case Western Reserve UniversityTatiana S. Morozkina - Case Western Reserve UniversitySpencer T. Burton - Case Western Reserve Univ, Dept Pediat Pulmonol, Cleveland, OH 44106 USATristan Lewis - University of GeorgiaTimothy Strassmaier - Nanion (Germany)Paulina Getsy - Case Western Reserve UniversityJames N. Bates - University of Iowa, AnesthesiaStephen J. Lewis - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.5(18), e134174
- DOI
- 10.1172/jci.insight.134174
- PMID
- 32790645
- PMCID
- PMC7526540
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 15
- Grant note
- Riley Children's Foundation 1P01HL101871; 1 P01HL128192; T32HL125245; SIG RR016789 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Eli Lilly Foundation INCITE Grant; Eli Lilly Children's Lung Foundation Harrington Discovery Institute
- Language
- English
- Date published
- 09/17/2020
- Academic Unit
- Anesthesia
- Record Identifier
- 9984425351102771
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