Heterogeneous functional expression of the sustained inward Na⁺ current in guinea pig sinoatrial node cells

The sustained inward Na⁺ current (I _st) identified in the sinoatrial node (SAN) cell has been suggested to play a pivotal role in cardiac pacemaking. However, the composition of cells in the SAN is heterogeneous and cell-to-cell variability in the magnitude of I _st remains to be fully characterized. The present study investigated the current density of I _st in morphologically different types of pacemaker cells dissociated from guinea pig SAN. I _st was preferentially detected in spontaneously active spindle or spider-shaped cells, but was less well expressed in larger-sized elongated spindle-type cells and practically absent in clearly striated atrial-like cells, despite clear expression of the funny current (I _f). The current density of I _st in spindle and spider cells varied from 0.7 to 1.6 pA pF^-1 and was significantly reduced in non-beating cells with similar morphologies. By linear regression analysis, we identified a positive correlation between the current densities of I _st and the L-type Ca²⁺ current (I _Ca,L), which was specifically observed in spindle and spider cells. These cells exhibited a more negative voltage for half maximal I _Ca,L activation than atrial-like cells, suggesting a variable ratio between Ca_V1.2- and Ca_V1.3-mediated I _Ca,L in SAN cells. Consistent single-cell transcript measurements confirmed a higher relative expression of Ca_V1.3, which activates at more negative potentials, in spindle cells than in atrial-like cells. Taken together, these results can be interpreted as indicating that I _st plays a specific role in primary pacemaker cells and that its presence is closely correlated with functional levels of Ca_V1.3-mediated I _Ca,L.