Regional differences in the expression of tetrodotoxin-sensitive inward Ca(2+) and outward Cs(+)/K(+) currents in mouse and human ventricles

Tetrodotoxin (TTX) sensitive inward Ca(2+) currents, I(Ca(TTX)), have been identified in cardiac myocytes from several species, although it is unclear if I(Ca(TTX)) is expressed in all cardiac cell types, and if I(Ca(TTX)) reflects Ca(2+) entry through the main, Nav1.5-encoded, cardiac Na(+) (Nav) channels. To address these questions, recordings were obtained with 2 mm Ca(2+) and 0 mm Na(+) in the bath and 120 mm Cs(+) in the pipettes from myocytes isolated from adult mouse interventricular septum (IVS), left ventricular (LV) endocardium, apex, and epicardium and from human LV endocardium and epicardium. On membrane depolarizations from a holding potential of −100 mV, I(Ca(TTX)) was identified in mouse IVS and LV endocardial myocytes and in human LV endocardial myocytes, whereas only TTX-sensitive outward Cs(+)/K(+) currents were observed in mouse LV apex and epicardial myocytes and human LV epicardial myocytes. The inward Ca(2+), but not the outward Cs(+)/K(+), currents were blocked by mm concentrations of MTSEA, a selective blocker of cardiac Nav1.5-encoded Na(+) channels. In addition, in Nav1.5-expressing tsA-201 cells, I(Ca(TTX)) was observed in 3 (of 20) cells, and TTX-sensitive outward Cs(+)/K(+) currents were observed in the other (17) cells. The time- and voltage-dependent properties of the TTX-sensitive inward Ca(2+) and outward Cs(+)/K(+) currents recorded in Nav1.5-expressing tsA-201 were indistinguishable from native currents in mouse and human cardiac myocytes. Overall, the results presented here suggest marked regional, cell type-specific, differences in the relative ion selectivity, and likely the molecular architecture, of native SCN5A-/Scn5a- (Nav1.5-) encoded cardiac Na(+) channels in mouse and human ventricles.