Pacemaker Cells of the Atrioventricular Node are CaV1.3 Dependent Oscillators

Abstract

The atrioventricular node (AVN) can generate pacemaker activity in case of failure of the sino-atrial node (SAN). However, the mechanisms underlying pacemaking in AVN cells (AVNCs) are poorly understood. Voltage-dependent ion channels such as hyperpolarization-activated HCN channels, L-type Cav1.3 and T-type Cav3.1 channels are known to play a role in pacemaking of sino-atrial node cells (SANCs). Here, we investigate the role of these channels in AVNCs pacemaker activity using genetically modified mouse strains and show that they differentially impact pacemaking of AVNCs than of SANCs. Indeed, contrary to SANCs, Cav1.3 channels are necessary for pacemaking of AVNCs and accounted for the predominant fraction of ICa,L. Inactivation of Cav3.1 channels impaired automaticity in AVNCs by promoting sporadic block of automaticity and spontaneous cellular arrhythmia.Abolition of the cAMP sensitivity of HCN channels shifted the If activation to voltages negative to that spanning the diastolic depolarization and prevented AVNCs automaticity in basal conditions. However pacemaker activity could be restored to control levels by adrenergic receptor stimulation.Inactivation of both Cav1.3 and Cav3.1 results in abolishment of pacemaking. Inhibition of TTX-resistant (INar) Na+ current showed that this is a key contributor of the action potential (AP) threshold and upstroke velocity.Conclusion: 1. Spontaneous firing rate in AVNCs is strongly dependent from Cav1.3-mediated L type calcium current and from TTX resistant sodium current (INa,r). 2. In AVNCs the Cav1.3 isoform seems to be predominant compared to Cav1.2 isoform. 3. The fact that hyperpolarization of Cav1.3-/-AVNCs pacemaking can be observed suggests that the absence of pacemaker activity is not due to the impossibility to generate the upstroke phase of the AP but probably due to an imbalance between outward and inward currents during the diastolic depolarization.