title: Distribution and function of sodium channel subtypes in human atrial myocardium.
abstract: Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac muscle. However, their localization and expression patterns in human myocardium have not yet been clearly defined. We used immunohistochemical methods to define the level of expression and the subcellular localization of sodium channel α and β subunits in human atrial myocytes. Nav1.2 channels are located in highest density at intercalated disks where β1 and β3 subunits are also expressed. Nav1.4 and the predominant Nav1.5 channels are located in a striated pattern on the cell surface at the z-lines together with β2 subunits. Nav1.1, Nav1.3, and Nav1.6 channels are located in scattered puncta on the cell surface in a pattern similar to β3 and β4 subunits. Nav1.5 comprised approximately 88% of the total sodium channel staining, as assessed by quantitative immunohistochemistry. Functional studies using whole cell patch-clamp recording and measurements of contractility in human atrial cells and tissue showed that TTX-sensitive (non-Nav1.5) α subunit isoforms account for up to 27% of total sodium current in human atrium and are required for maximal contractility. Overall, our results show that multiple sodium channel α and β subunits are differentially localized in subcellular compartments in human atrial myocytes, suggesting that they play distinct roles in initiation and conduction of the action potential and in excitation-contraction coupling. TTX-sensitive sodium channel isoforms, even though expressed at low levels relative to TTX-sensitive Nav1.5, contribute substantially to total cardiac sodium current and are required for normal contractility. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Susann G
authors.initials: SG
authors.lastname: Kaufmann
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Westenbroek
authors.affiliation: Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Maass
authors.affiliation: Thoracic Surgery, Hospital St. Raphael, Ostercappeln, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Lange
authors.affiliation: Thoracic and Cardiovascular Surgery, Heart and Diabetes Center, Bad Oeynhausen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Renner
authors.affiliation: Department of Physiology, University Würzburg, Würzburg, Germany.
authors.forename: Erhard
authors.initials: E
authors.lastname: Wischmeyer
authors.affiliation: Center for Cardiology, Lüneburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bonz
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Muck
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany.|Department of Medicine II, Hospital St. Elisabeth Straubing, Straubing, Germany.
authors.forename: Sebastian K G
authors.initials: SKG
authors.lastname: Maier
mesh_terms: D018031:Connexin 43 / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D009928:Organ Specificity; D021122:Protein Subunits / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human; D021122:Protein Subunits; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D013779:Tetrodotoxin
keywords: Contractility; Immunocytochemistry; Myocardium; Sodium channels