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Nitroxyl (HNO) targets phospholamban cysteines 41 and 46 to enhance cardiac function

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dc.contributor.authorKeceli, Gizemen
dc.contributor.authorMajumdar, Ananyaen
dc.contributor.authorThorpe, Chevon N.en
dc.contributor.authorJun, Seunghoen
dc.contributor.authorTocchetti, Carlo G.en
dc.contributor.authorLee, Dongen
dc.contributor.authorMahaney, James E.en
dc.contributor.authorPaolocci, Nazarenoen
dc.contributor.authorToscano, John P.en
dc.date.accessioned2021-10-14T18:44:08Zen
dc.date.available2021-10-14T18:44:08Zen
dc.date.issued2019-06-01en
dc.date.updated2021-10-14T18:44:04Zen
dc.description.abstractNitroxyl (HNO) positively modulates myocardial function by accelerating Ca2+ reuptake into the sarcoplasmic reticulum (SR). HNO-induced enhancement of myocardial Ca2+ cycling and function is due to the modification of cysteines in the transmembrane domain of phospholamban (PLN), which results in activation of SR Ca2+-ATPase (SERCA2a) by functionally uncoupling PLN from SERCA2a. However, which cysteines are modified by HNO, and whether HNO induces reversible disulfides or single cysteine sulfinamides (RS(O)NH2) that are less easily reversed by reductants, remain to be determined. Using an 15N-edited NMR method for sulfinamide detection, we first demonstrate that Cys46 and Cys41 are the main targets of HNO reactivity with PLN. Supporting this conclusion, mutation of PLN cysteines 46 and 41 to alanine reduces the HNO-induced enhancement of SERCA2a activity. Treatment of WT-PLN with HNO leads to sulfinamide formation when the HNO donor is in excess, whereas disulfide formation is expected to dominate when the HNO/thiol stoichiometry approaches a 1:1 ratio that is more similar to that anticipated in vivo under normal, physiological conditions. Thus, 15N-edited NMR spectroscopy detects redox changes on thiols that are unique to HNO, greatly advancing the ability to detect HNO footprints in biological systems, while further differentiating HNO-induced post-translational modifications from those imparted by other reactive nitrogen or oxygen species. The present study confirms the potential of HNO as a signaling molecule in the cardiovascular system.en
dc.description.versionPublished versionen
dc.format.extentPages 758-770en
dc.format.extent13 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1085/jgp.201812208en
dc.identifier.eissn1540-7748en
dc.identifier.issn0022-1295en
dc.identifier.issue6en
dc.identifier.orcidThorpe, Chevon [0000-0003-4328-7876]en
dc.identifier.otherjgp.201812208 (PII)en
dc.identifier.pmid30842219en
dc.identifier.urihttp://hdl.handle.net/10919/105388en
dc.identifier.volume151en
dc.language.isoenen
dc.publisherRockefeller University Pressen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000470084100009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution-NonCommercial-ShareAlike 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectPhysiologyen
dc.subjectNMR SOLUTION STRUCTUREen
dc.subjectMONOMERIC PHOSPHOLAMBANen
dc.subjectRYANODINE RECEPTORen
dc.subjectPROTEIN-STRUCTUREen
dc.subjectACTIVATES SERCAen
dc.subjectHYBRID SOLUTIONen
dc.subjectLIPID-BILAYERSen
dc.subjectPHOSPHORYLATIONen
dc.subjectCA2+-ATPASEen
dc.subjectSITEen
dc.subject0606 Physiologyen
dc.subject1116 Medical Physiologyen
dc.subjectPhysiologyen
dc.subject.meshSarcoplasmic Reticulumen
dc.subject.meshMyocardiumen
dc.subject.meshCardiovascular Systemen
dc.subject.meshAnimalsen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMiceen
dc.subject.meshCalciumen
dc.subject.meshNitrogen Oxidesen
dc.subject.meshReactive Nitrogen Speciesen
dc.subject.meshReactive Oxygen Speciesen
dc.subject.meshCysteineen
dc.subject.meshCalcium-Binding Proteinsen
dc.subject.meshProtein Processing, Post-Translationalen
dc.subject.meshOxidation-Reductionen
dc.subject.meshMaleen
dc.titleNitroxyl (HNO) targets phospholamban cysteines 41 and 46 to enhance cardiac functionen
dc.title.serialJournal of General Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2019-02-15en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen

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