Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome

Simple item page
dc.contributor.authorSong, LouJinen
dc.contributor.authorBekdash, Ramseyen
dc.contributor.authorMorikawa, Kumien
dc.contributor.authorQuejada, Jose R.en
dc.contributor.authorKlein, Alison D.en
dc.contributor.authorAina-Badejo, Danielleen
dc.contributor.authorYoshida, Kazushigeen
dc.contributor.authorYamamoto, Hannah E.en
dc.contributor.authorChalan, Amyen
dc.contributor.authorYang, Risakoen
dc.contributor.authorPatel, Achchheen
dc.contributor.authorSirabella, Darioen
dc.contributor.authorLee, Teresa M.en
dc.contributor.authorJoseph, Leroy C.en
dc.contributor.authorKawano, Fuunen
dc.contributor.authorWarren, Junco S.en
dc.contributor.authorSoni, Rajesh K.en
dc.contributor.authorMorrow, John P.en
dc.contributor.authorYazawa, Masayukien
dc.date.accessioned2023-01-17T14:07:46Zen
dc.date.available2023-01-17T14:07:46Zen
dc.date.issued2022-02-17en
dc.date.updated2023-01-14T14:33:18Zen
dc.description.abstractSome missense gain-of-function mutations in <i>CACNA1C</i> gene, encoding calcium channel Ca<sub>V</sub>1.2, cause a life-threatening form of long QT syndrome named Timothy syndrome, with currently no clinically-effective therapeutics. Here we report that pharmacological targeting of sigma non-opioid intracellular receptor 1 (SIGMAR1) can restore electrophysiological function in iPSC-derived cardiomyocytes generated from patients with Timothy syndrome and two common forms of long QT syndrome, type 1 (LQTS1) and 2 (LQTS2), caused by missense trafficking mutations in potassium channels. Electrophysiological recordings demonstrate that an FDA-approved cough suppressant, dextromethorphan, can be used as an agonist of SIGMAR1, to shorten the prolonged action potential in Timothy syndrome cardiomyocytes and human cellular models of LQTS1 and LQTS2. When tested <i>in vivo</i>, dextromethorphan also normalized the prolonged QT intervals in Timothy syndrome model mice. Overall, our study demonstrates that SIGMAR1 is a potential therapeutic target for Timothy syndrome and possibly other inherited arrhythmias such as LQTS1 and LQTS2.en
dc.description.versionAccepted versionen
dc.format.extentPages 142-156en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s44161-021-00016-2en
dc.identifier.eissn2731-0590en
dc.identifier.issn2731-0590en
dc.identifier.issue2en
dc.identifier.orcidWarren, Junko [0000-0001-5231-4181]en
dc.identifier.otherPMC9431959en
dc.identifier.pmid36051854en
dc.identifier.urihttp://hdl.handle.net/10919/113192en
dc.identifier.volume1en
dc.language.isoenen
dc.publisherSpringeren
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36051854en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectClinical Researchen
dc.subjectOrphan Drugen
dc.subjectStem Cell Research - Induced Pluripotent Stem Cell - Humanen
dc.subjectRare Diseasesen
dc.subjectGeneticsen
dc.subjectStem Cell Research - Induced Pluripotent Stem Cellen
dc.subjectCardiovascularen
dc.subjectHeart Diseaseen
dc.subjectStem Cell Researchen
dc.subject2.1 Biological and endogenous factorsen
dc.subject5 Development of treatments and therapeutic interventionsen
dc.subject5.1 Pharmaceuticalsen
dc.subject2 Aetiologyen
dc.titleSigma non-opioid receptor 1 is a potential therapeutic target for long QT syndromeen
dc.title.serialNature Cardiovascular Researchen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherresearch-articleen
dc.type.otherJournal Articleen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Song_Nature_Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.pdf
Size:
6.57 MB
Format:
Adobe Portable Document Format
Description:
Accepted version
Download

Collections

All Faculty Deposits
Scholarly Works, Fralin Biomedical Research Institute at VTC