title: Biophysical, Molecular, and Pharmacological Characterization of Voltage-Dependent Sodium Channels From Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
abstract: The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current-voltage curves used hiPSC-CM to model voltage-gated Na+channel (Nav) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Navchannels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Navchannels from hiPSC-CM and assess the appropriateness of this novel cell model.
  
  
  
  We generated hiPSC-CM using the recently described monolayer-based differentiation protocol.
  
  
  
  hiPSC-CM expressed cardiac-specific markers, exhibited spontaneous electrical and contractile activities, and expressed distinct Navchannels subtypes. Electrophysiological, pharmacological, and molecular characterizations revealed that, in addition to the main Nav1.5 channel, the neuronal tetrodotoxin (TTX)-sensitive Nav1.7 channel was also significantly expressed in hiPSC-CM. Most of the Na+currents were resistant to TTX block. Therapeutic concentrations of lidocaine, a class I antiarrhythmic drug, also inhibited Na+currents in a use-dependent manner. Nav1.5 and Nav1.7 expression and maturation patterns of hiPSC-CM and native human cardiac tissues appeared to be similar. The 4 Navβ regulatory subunits were expressed in hiPSC-CM, with β3 being the preponderant subtype.
  
  
  
  The findings indicated that hiPSC-CM robustly express Nav1.5 channels, which exhibited molecular and pharmacological properties similar to those in native cardiac tissues. Interestingly, neuronal Nav1.7 channels were also expressed in hiPSC-CM and are likely to be responsible for the TTX-sensitive Navcurrent.
authors.affiliation: Centre de recherche de l'Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada.
authors.forename: Adrien
authors.initials: A
authors.lastname: Moreau
authors.affiliation: Centre de recherche de l'Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Mercier
authors.affiliation: Centre de recherche de l'Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thériault
authors.affiliation: Cardiovascular Research Program, VA New York Harbor Healthcare, Brooklyn, New York, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boutjdir
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Bettina
authors.initials: B
authors.lastname: Burger
authors.affiliation: Cardiology and Emergency Departments, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Dagmar I
authors.initials: DI
authors.lastname: Keller
authors.affiliation: Centre de recherche de l'Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada; Department of Medicine, Université Laval, Quebec City, Quebec, Canada. Electronic address: mohamed.chahine@phc.ulaval.ca.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
mesh_terms: D001669:Biochemical Phenomena; D055592:Biophysical Phenomena; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000378:metabolism / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015222:Sodium Channels; D061566:Voltage-Gated Sodium Channels