Beyond pacemaking: HCN channel functions in the sinoatrial node

The human heart beats up to three billion times throughout life, with very high precision and usually without a break. The sinoatrial node (SAN) is the primary pacemaker of the heart. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depends on the slope of their slow diastolic depolarization (SDD). To adapt cardiac output to physical demands, heart rate (HR) is regulated by the autonomic nervous system by accelerating or decelerating SDD via changes in cAMP concentration in pacemaker cells – a process called chronotropic effect. Intuitively, one would assume that all pacemaker cells in the SAN fire simultaneously and at the same frequency to generate a common network rhythm. However, our research has shown that there are subdivisions of pacemaker cell regions within the SAN characterized by different firing rates and firing behavior. This includes nonfiring or dormant pacemaker cells that fulfill important physiological functions in the SAN and are necessary to ensure smooth HR transitions during the chronotropic response. Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are the molecular correlate of the If current and contribute significantly to the SDD and firing behaviour of pacemaker cells. While the highly cAMP-sensitive HCN4 channels are expressed throughout the entire SAN tissue, the less cAMP-sensitive HCN1 channels are found only in the central region. Using a knock-in mouse model with HCN4 channels that are insensitive to cAMP we were able to show that regulation of HCN4 by cAMP contributes to the control of the number of non-firing cells rather than changing the frequency of firing cells. Thus, HCN4 pacemaker channels do not contribute substantially to the frequency-increasing effect of the chronotropic response, but they do control other important aspects of the chronotropic effect, such as stabilization of basal HR and HR transitions, as well as dampening of ANS input and limiting maximal HR reduction by the vagal nerve. Surprisingly, cAMP regulation of HCN1 channels cells appears to play a more critical role than expected in controlling HR. Knock-in mice with cAMP-insensitive HCN1 channels show chronotropic incompetence and a reduced dynamic HR range. In addition, using a knockout mouse model lacking HCN1, we have shown that HCN1 channels are essential for synchronisation of pacemaker cells, thereby stabilising heart rate and reducing heart rate variability.