Abstract
ABSTRACTTetrodotoxin (TTX) sensitive inward Ca2+ currents, ICa(TTX), have been identified in cardiac myocytes from several species, although it is unclear if ICa(TTX) is expressed in all cardiac cell types, and if ICa(TTX) reflects Ca2+ entry through the main, Nav1.5-encoded, cardiac Na+ (Nav) channels. To address these questions, recordings were obtained with 2 mm Ca2+ 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, ICa(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 Ca2+, 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, ICa(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 Ca2+ 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.
Highlights
Inward calcium (Ca2+) currents that are sensitive to the voltage-gated sodium (Na+) channel toxin, tetrodotoxin (TTX), ICa(TTX), have been described in neuronal [1,2,3] and cardiac [4,5,6,7] cells
We used a combination of electrophysiological and pharmacological approaches to test the hypothesis that ICa(TTX) is differentially expressed in native ventricular myocardium. These experiments revealed marked differences in the densities of ICa(TTX) and of TTXsensitive outward Cs+/K+ currents in myocytes isolated from adult mouse interventricular septum (IVS), left ventricular (LV) endocardium, apex, and epicardium, as well as in human LV endocardial and epicardial myocytes
Similar to the findings in myocytes (Figure 3), the TTXsensitive inward Ca2+ and outward Cs+/K+ currents in Nav1.5-expressing tsA-201 cells were blocked by MTSEA
Summary
Inward calcium (Ca2+) currents that are sensitive to the voltage-gated sodium (Na+) channel toxin, tetrodotoxin (TTX), ICa(TTX), have been described in neuronal [1,2,3] and cardiac [4,5,6,7] cells. The results of experiments conducted on adult rat ventricular cells incubated with an antisense oligonucleotide directed against rat Scn5a have been interpreted as suggesting that a different (i.e. not Nav1.5) Nav α subunit underlies ICa(TTX) [20]. It has been suggested, that voltagegated cardiac Ca2+ channels, both high threshold, L-type Ca2+ channels [21,22,23] and low threshold, T-type Ca2+ channels [8,24], contribute to ICa(TTX)
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