Control of the fight-or-flight response of heart rate by L-type Cav1.3 (α1D) calcium channels

The mechanisms underlying the increase in the frequency of heartbeat induced by catecholamines, so called fight-or-flight response (FFR) of heart rate (HR), are incompletely understood. cAMP-dependent regulation of f-(HCN) channels, underlying the “funny” current (If), and ryanodine receptor 2 (RyR2)-mediated Ca2+ release are considered as the predominant mechanisms of HR FFR. However, it is showed that If contributes to setting the basal HR, but is not required for the sympathetic regulation of pacemaking. In addition, impairment of RyR2-mediated [Ca2+]i release by ryanodine only reduces β-adrenergic regulation of pacemaker activity, suggesting that other mechanism(s) are involved in the generation of HR FFR. We have shown that L-type Cav1.3 calcium channels are required for β-adrenergic mediated initiation of firing in dormant sino-atrial node (SAN) pacemaker cells. To define the role of Cav1.3 channels in the FFR of HR and SAN automaticity. We crossed mice deficient in Cav1.3 channels (Cav1.3-/-) with mice (CNBD) lacking cAMP sensitivity of f-channels. In vivo and in isolated hearts ECG recordings were performed. Automaticity and diastolic current of SAN cells were evaluated using patch-clamp technique. Cav1.3-/- and CNBD mice displayed bradycardia at rest, but similar degree of increase in HR after β-adrenergic stimulation by injection of isoproterenol (ISO) in comparison to WT mice. However, Cav1.3-/-/CNBD mice did not show significant HR increase in vivo after injection of ISO or during physical exercise. ISO failed to increase the rate in isolated herats and in the SAN cells from Cav1.3-/-/CNBD mice. Consistent with these data, mutant mice in which L-type Cav1.2 channels have been rendered insensitive to dihydropyridines (Cav1.2DHP-/-) showed that concomitant selective pharmacologic inhibition of Cav1.3 and cAMP-dependent dependent regulation of f-HCN channels by the di-cyclic nucleotide di-cGMP prevented the positive chronotropic response to ISO of SAN cells automaticity. Under the same conditions, ISO did not significantly increase diastolic current, explaining loss of SAN FFR. Our study identifies L-type Cav1.3 channels as key effectors of β-adrenergic regulation of SAN automaticity with If.