Aim: 

The spontaneous activity of pacemaker cells in the sino-atrial node (SAN) controls the heart rhythm and rate (HR) under physiological conditions. SAN cells express a wide array of ionic channels, but we have limited knowledge about their functional role in the genesis and regulation of heart automaticity.

Methods: 

We have studied pacemaker activity in mice lacking L-type Ca_v1.3 (Ca_v1.3^-/-) and T-type Ca_v3.1 (Ca_v3.1^-/-) Ca²⁺ channels.

Results: 

We found severely slowed and erratic pacemaking in SAN and atrioventricular node (AVN) cells from Ca_v1.3^-/- mice and attributed this phenomenon to abolition of I_Ca,L in the diastolic depolarization range. In contrast, disruption of the gene coding for Ca_v3.1 channels abolished I_Ca,T in SAN and AVN cells. Ca _v3.1^-/-- mice had moderately reduced HR and slowed AVN conduction. The differential role of Ca _v1.3 channels and "funny" f-channels (underlying the cardiac I_f current) in the genesis and regulation of cardiac automaticity was then studied. The f-channel blocker ivabradine was administrated intra-peritoneally to different mouse strains. In WT and Ca _v1.3^-/- mice, ivabradine dose-dependently reduced the mean HR. At 3 mg/kg, mean HR reduction was –23 and –39% in WT and Ca _v1.3^-/-, respectively.

Conclusions: 

Similarly to f-channels, Ca_v1.3 channels controls basal and maximal HR, and in addition, play a distinct role in stabilizing HR. Furthermore, both normal and intrinsic pacemaker activity can persist in the absence of Ca_v1.3 channels even after strong inhibition of f-channels. In conclusion, our work demonstrates that multiple voltage-gated Ca²⁺ channel mechanisms contribute to cardiac automaticity and deserve distinct roles with respect to "pacemaker" f-channels.