Matteo MANGONI

Catecholamines increase the heart rate via L-type Cav1.3 (alpha1D) and ‘funny’ f-(HCN) channels

The role of ion channels in heartbeat quickening by catecholamines is not understood. We show that sinoatrial node L-type Cav1.3 and hyperpolarization-activated HCN4 channels are the ionic underpin of beta-adrenergic receptor activation of heart rate. Mutant mice carrying ablation of Cav1.3 and expressing dominant-negative cAMP-insensitive HCN4 subunits in the heart lack diurnal variation in heart rate and fail to increase heartbeat after administration of catecholamines, or during physical activity. Consistently, selective pharmacologic inhibition of Cav1.3 prevents catecholaminergic increase in pacemaker activity when cAMP-dependent regulation of HCN4 was abolished, or upon interference with cAMP-mediated molecular movement of HCN4 c-linker structure in the channel c-terminus. Phosphorylation of the small RGK G protein Rad was required for Cav1.3 to increase pacemaker activity under β-adrenergic activation. Or study identifies Cav1.3 and HCN4 channels as the key effectors of β-adrenergic regulation of sinoatrial pacemaker explaining the ionic mechanism underlying the “flight-or-fight” response of the heartbeat.