Project presentation 2020

cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells

Fenske S, Hennis K, Roetzer R, Brox V, Becirovic E, Scharr A, Gruner C, Ziegler T, Mehlfeld V, Brennan J, Efimov I, Pauza A, Moser M, Wotjak C, Kupatt C, Goenner R, Zhang R, Zhang H, Zong X, Biel M*, Wahl- Schott* C.

Pacemaker channels are representatives of hyperpolarization-activated and cyclic nucleotide-gated (HCN) cation channels and are considered essential motors for the generation of the heartbeat in the sinoatrial node (SAN) of the heart. Four representatives, HCN1-HCN4, are found in humans and mice. HCN4 is the main isoform and is expressed throughout the SAN. HCN channels are opened by hyperpolarization. In addition, activation of the channels is regulated by cyclic adenosine monophosphate (cAMP). An increase in the intracellular cAMP concentration, as occurs when the sympathetic nervous system is activated, leads to an increase in HCN channel activity. In the Research Report 2021, we present a project that is being carried out in the group of physiologist and pharmacologist Christian Wahl-Schott from the Institute of Neurophysiology at the MHH in collaboration with the pharmacologists Stefanie Fenske and Martin Biel of the Chair Pharmacology for Natural Sciences at the Department of Pharmacy at LMU Munich and published in the journal Nature Communications. In the study, the authors discovered how the secondary messenger cAMP regulates the heartbeat via an effect on HCN4 channels.

To investigate the role ofcAMP-dependent regulation(CDR) of HCN4, the research team produced knock-in mice in which cAMP can no longer bind to HCN4 (HCN4FEA mouse line). When studying individual pacemaker cells from the SAN, the scientists discovered that SAN cells can not only adopt a long-known activity mode in which the cells fire action potentials and drive the heartbeat(firing mode), but can also adopt a non-firing mode in which the cells stand still for a period of up to one minute. In the network of the sinus node, the number of cells in non-firing mode is set by the CDR. Pacemaker cells in non-firing mode act as "brakes" in the SAN network, inhibiting the activity of neighboring pacemaker cells in firing mode. It is known that inhibitory elements generally increase the stability of electrically active networks. In the brain, for example, inhibitory neurons stabilize the activity of neuronal network connections.

Video: Beating atrium with sinus node region in a preparation from the mouse.

The current work shows that inhibitory control of excitability is also required in the sinus node for stable pacemaker function. Both the overactivity and the lack of inhibitory control lead to a massive disturbance of the pacemaker function of the heart, which manifests itself as "sick sinus node" syndrome (see figure). The CDR of HCN4 can be used to set the exact dose for inhibition within the sinus node according to the situation. As a result, the heart rate can be effectively stabilized and both bradycardia and tachyarrhythmia can be counteracted.

In summary, this study shows that the CDR of HCN4 is important for the control of the SAN by the autonomic nervous system, in particular for a safe transition from a stable baseline heart rate to a new target rate during sympathetic and/or parasympathetic activity. The CDR of HCN4 appears to be particularly important in fine-tuning the heart rate-lowering effect of the parasympathetic nervous system. The CDR counteracts parasympathetic overdrive, an inappropriate drop in heart rate and the occurrence of bradycardia.