title: Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia.
abstract: Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca(2+)]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca(2+)]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca(2+). Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca(2+)]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na(+)-Ca(2+) exchange. These results suggest that LQTS mutations act partly on cytosolic Ca(2+) cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: C Ian
authors.initials: CI
authors.lastname: Spencer
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Departments of Medicine, Anatomy and Cellular and Molecular Pharmacology, University of California San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Shiro
authors.initials: S
authors.lastname: Baba
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Departments of Medicine, Anatomy and Cellular and Molecular Pharmacology, University of California San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Hua
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Marie A F
authors.initials: MA
authors.lastname: Sears
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Departments of Bioengineering, and Material Science and Engineering, University of California, Berkeley, CA 94720, USA.
authors.forename: Chi-cheng
authors.initials: CC
authors.lastname: Fu
authors.affiliation: Stem Cell and Regenerative Medicine Center, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Stem Cell and Regenerative Medicine Center, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Sadguna
authors.initials: S
authors.lastname: Balijepalli
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tomoda
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Paweena
authors.initials: P
authors.lastname: Lizarraga
authors.affiliation: Departments of Medicine, Anatomy and Cellular and Molecular Pharmacology, University of California San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Julianne
authors.initials: J
authors.lastname: Wojciak
authors.affiliation: Departments of Medicine, Anatomy and Cellular and Molecular Pharmacology, University of California San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Scheinman
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Institute of Biomedical Technology, University of Tampere, Biokatu 12, 33520 Tampere, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Aalto-Setälä
authors.affiliation: Stem Cell and Regenerative Medicine Center, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.affiliation: Stem Cell and Regenerative Medicine Center, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.affiliation: Departments of Bioengineering, and Material Science and Engineering, University of California, Berkeley, CA 94720, USA.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Healy
authors.affiliation: Stem Cell and Regenerative Medicine Center, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Departments of Medicine, Anatomy and Cellular and Molecular Pharmacology, University of California San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: bconklin@gladstone.ucsf.edu.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conklin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007231:Infant, Newborn; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D002110:Caffeine; D009543:Nifedipine; D002118:Calcium