Regional differences in the expression of tetrodotoxin-sensitive inward Ca2+ and outward Cs+/K+ currents in mouse and human ventricles

Channels (Austin). 2019 Dec;13(1):72-87. doi: 10.1080/19336950.2019.1568146.


Tetrodotoxin (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.

Keywords: LV endocardium; LV epicardium; Left ventricles (LV); Nav1.5; interventricular septum; voltage-gated Na currents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cesium / metabolism*
  • Electric Conductivity*
  • Female
  • Heart Ventricles / drug effects*
  • Heart Ventricles / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Potassium / metabolism*
  • Sodium / metabolism
  • Tetrodotoxin / pharmacology*


  • Cesium
  • Tetrodotoxin
  • Sodium
  • Potassium
  • Calcium