Song, LouJinBekdash, RamseyMorikawa, KumiQuejada, Jose R.Klein, Alison D.Aina-Badejo, DanielleYoshida, KazushigeYamamoto, Hannah E.Chalan, AmyYang, RisakoPatel, AchchheSirabella, DarioLee, Teresa M.Joseph, Leroy C.Kawano, FuunWarren, Junco S.Soni, Rajesh K.Morrow, John P.Yazawa, Masayuki2023-01-172023-01-172022-02-172731-0590PMC9431959http://hdl.handle.net/10919/113192Some missense gain-of-function mutations in <i>CACNA1C</i> gene, encoding calcium channel Ca_V1.2, 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.Pages 142-156application/pdfenIn CopyrightClinical ResearchOrphan DrugStem Cell Research - Induced Pluripotent Stem Cell - HumanRare DiseasesGeneticsStem Cell Research - Induced Pluripotent Stem CellCardiovascularHeart DiseaseStem Cell Research2.1 Biological and endogenous factors5 Development of treatments and therapeutic interventions5.1 Pharmaceuticals2 AetiologyArticle - Refereed2023-01-14https://doi.org/10.1038/s44161-021-00016-212Warren, Junko [0000-0001-5231-4181]360518542731-0590