Distinct subcellular localization of different sodium channel α and β subunits in single ventricular myocytes from mouse heart

Background - Voltage-gated sodium channels composed of pore-forming alpha and auxiliary beta subunits are responsible for the rising phase of the action potential in cardiac muscle, but their localizations have not yet been clearly defined. Methods and Results - Immunocytochemical studies show that the principal cardiac alpha subunit isoform Na(v)1.5 and the beta2 subunit are preferentially localized in intercalated disks, identified by immunostaining of connexin 43, the major protein of cardiac gap junctions. The brain alpha subunit isoforms Na(v)1.1, Na(v)1.3, and Na(v)1.6 are preferentially localized with beta1 and beta3 subunits in the transverse tubules, identified by immunostaining of alpha-actinin, a cardiac z-line protein. The beta1 subunit is also present in a small fraction of intercalated disks. The recently cloned beta4 subunit, which closely resembles beta2 in amino acid sequence, is also expressed in ventricular myocytes and is localized in intercalated disks as are beta2 and Na(v)1.5. Conclusions - Our results suggest that the primary sodium channels present in ventricular myocytes are composed of Na(v)1.5 plus beta2 and/ or beta4 subunits in intercalated disks and Na(v)1.1, Na(v)1.3, and Na(v)1.6 plus beta1 and/ or beta3 subunits in the transverse tubules.