Abstract
The heart is a spontaneously active organ whose contractile activity is dependent of a spontaneous intrinsic electrical activity, which refers to one of the fundamental cardiac properties: cardiac automaticity. The electrical signal is generated in the sino-atrial node tissue (SAN) and is then propagated throughout the heart, triggering cardiomyocytes contraction. Cardiac automaticity relies on the capacity of pacemaker sino-atrial node cells (SANC) to spontaneously depolarize (diastolic depolarization, DD) which brings membrane potential to the threshold of the sinoatrial action potential (AP). Complex and not entirely understood yet, diastolic depolarization results from a robust interplay of membrane ion channels activity (hyperpolarization-activated HCN4 channels, L-type Cav1.3 and T-type Cav3.1 calcium channels) and intracellular calcium dynamics with spontaneous local calcium releases (LCRs) from the sarcoplasmic reticulum via the ryanodine receptors (RyR). By triggering cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) catecholaminergic stimulation of pacemaker activity by sympathetic autonomic nervous system accelerates the firing frequency of SANC.The objective of my PhD was to determine the role of L-type Cav1.3 calcium channels in the catecholaminergic regulation of SANC. Patch-clamp experiments on isolated mouse SANC showed that pharmacologic inhibition of Cav1.3 channels completely reversed the effects of adrenergic stimulation on the frequency. Imaging of intracellular calcium further revealed that LCRs synchronization under activation of adrenergic receptors was dependent of Cav1.3 channels activity. Hence, L-type Cav1.3 calcium channels seem to be the main mediator of the positive chronotropic response of pacemaker activity in mouse SANC.