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

Tetrodotoxin (TTX) sensitive inward Ca currents, I, have been identified in cardiac myocytes from several species, although it is unclear if I is expressed in all cardiac cell types, and if I reflects Ca entry through the main, Nav1.5-encoded, cardiac Na (Nav) channels. To address these questions, recordings were obtained with 2 mm Ca 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 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, 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 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 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.