Cardiac pacemaking relies on the spontaneous electrical activity of sino-atrial myocytes (SANCs) in the right atrium arising from a robust interplay of membrane ion channels activity (membrane clock) and intracellular calcium dynamics (calcium clock). Strikingly, most of isolated SANCs exhibit a dormant state (no apparent spontaneous activity) whereas only a small fraction shows regular firing. It has recently been shown that these non-firing SANCs are also present in intact SAN and can switch into a firing mode under beta-adrenergic stimulation. However, their functional relevance in vivo is unknown.

To study the role of L-type Ca_v1.3 calcium channels in dormant SANCs using a knock-in mouse strain in which the sensitivity of Ca_v1.2 α1 subunits to dihydropyridines (DHP) was inactivated (Ca_v1.2^DHP−/−).

We performed voltage and current-clamp recordings and confocal live imaging on isolated SANCs under isoprenaline (ISO, 100nM) in the absence or presence of the DHP blocker Nifedipine (Nife, 3μM).

Preliminary results seem to show less L-type calcium current I_Ca,L in dormant SANCs (D) compared to rhythmic SANCs (R) (D: −6.3±1.2, R: −15.6 pA/pF). Dormant SANCs also have less diastolic calcium (D: 96.9±12, R: 218±51.2 a.u, P=0.14) but significant higher sarcoplasmic reticulum calcium load (D: 6.3±0.6, R: 3.1±0.3 a.u, P=0.004). Interestingly, ISO perfusion could only switch half of dormant SANCs into a firing mode in both action potential (AP) and calcium transients (CT) recordings whereas the others remained dormant. Further Nife perfusion completely stopped this ISO-induced firing switching the cells back into a dormant state for the vast majority of them (75% in AP-recorded SANCs and 100% in CT-recorded SANCs).

Taken together, these results indicate that Cav1.3 channels play a key role in sustaining the coupling of membrane and calcium clock in dormant SANCs under beta-adrenergic stimulation.