HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of sinoatrial node

Abstract

The heart rate is dynamically controlled by the sympathetic and parasympathetic nervous systems that regulate the sinoatrial node (SAN). HCN4 pacemaker channels are well-known causative molecule of congenital sick sinus syndrome. Although HCN4 channels are activated by cAMP, the sympathetic response of SAN was preserved in the patients carrying loss-of-function mutations of HCN4 gene. In order to clarify the contribution of HCN4 channels in the autonomic regulation of SAN, we developed novel gain-of-function mutant mice in which expression level of HCN4 channels could be reversibly changed from zero to ∼3 times of that in wild type mice, using tetracycline trans-activator and tetracycline responsive element. Then, we recorded telemetric ECGs in free moving conscious mice, and analysed the heart rate variability (HRV). We also evaluated the response of SAN to cervical vagal nerve stimulation (CVNS). The conditional overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability. The HCN4-overexpression also attenuated bradycardia induced by the CVNS, only during the β-adrenergic stimulation. In contrast, the knockdown of HCN4 gave rise to sinus arrhythmia, and enhanced the parasympathetic response; complete sinus pause was induced by the CVNS. In vitro, we compared the effects of acetylcholine on the spontaneous action potentials of single pacemaker cells, and found that the similar phenotypic changes were induced by genetic manipulation of HCN4 expression both in the presence and absence of β-adrenergic stimulation. Our study suggests that HCN4 channels attenuate the vagal response of SAN, and thereby stabilize the spontaneous firing of SAN.

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