FIGURE 4.
Role of Cav1.3 channels for atrioventricular node (AVN) automaticity. Automaticity of wild-type (WT) AVN cells (AVNCs) is dependent on both INa and ICa,L. (a and b) Application of 20-μM tetrodotoxin (TTX) blocked action potential (AP) discharge. The membrane potential of AVNCs exposed to 20 μM TTX was stable at −59 ± 2 mV (n = 8). (c and d) Inhibition of ICa,L by 0.3 μM of the L-type channel blocker isradipine in WT mouse AVNCs stopped pacemaker activity of AVNCs and the cell membrane potential depolarized to −35 ± 3 mV (n = 6). Only low-amplitude oscillations of the membrane potential could be observed in isradipine-treated AVNCs. These results indicated that pacemaking of mouse AVNCs required both INa and ICa,L for AP discharge. (e) Cav1.3−/− AVNCs display positive membrane potential and low-amplitude oscillations without spontaneous APs very similar to isradipine-blocked WT AVNCs. (f) Tonic hyperpolarizing current injection (black arrow) induced spontaneous AP firing in Cav1.3−/− AVNCs but with slower pacemaker activity and smaller AP amplitude. This suggests contribution of Cav1.3 channels to both diastolic depolarization as well as to the AP itself. The positive resting membrane potential in Cav1.3−/− AVNCs likely is due to the loss of crosstalk between Cav1.3 channels and SK2 K+ channels. In the intact AVN, Cav1.3−/− myocytes must be sufficiently hyperpolarized (e.g., by electrical coupling with the right atrium) to enable INa-dependent APs and triggering by SAN impulses. (Reprinted with permission from Refs 103 and 104. Copyright 2011 Landes Bioscience)