The role of HCN channels for the synchronization process in the sinoatrial node of the heart

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Pacemaker channels are members of the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels and are considered essential motors for the generation of the heart beat in the sinoatrial node (SAN) of the heart. Four channel subtypes, HCN1-HCN4 are found in humans and mice. HCN4 represents the major 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). In this context, an increase in intracellular cAMP concentration, as it occurs during sympathetic nervous system activation, leads to an increase in HCN channel activity. In the previous proposal, we addressed the question how the secondary messenger cAMP regulates heartbeat via an effect on HCN4 channels. To address this question, we generated knock-in mice in which cAMP can no longer bind to HCN4. By studying single pacemaker cells from the SAN, we observed that SAN cells can not only adopt the well-known mode in which the cells fire spontaneous action potentials and drive the heartbeat (firing mode), but can also adopt a non-firing mode in which the cells remain quiescent for a period of up to 1 minute. We have evidence that pacemaker cells in non-firing mode act as "brakes" in the SAN network, inhibiting the activity of neighboring pacemaker cells in firing mode. Our hypothesis is that in the network of the SAN, the number of cells in non-firing mode is adjusted by the cAMP-dependent regulation of HCN4. Accordingly, the precise dose for inhibition within the sinus node could be adjusted according to the situation via the cAMP-dependent regulation of HCN4. Thus, heart rate could be effectively stabilized. Furthermore, we hypothesize that cAMP-dependent regulation of HCN1 and HCN2 may be of similar importance as cAMP-dependent regulation of HCN4. These hypotheses will be investigated in vitro and in vivo in this follow-up proposal. Taken together, we expect the findings obtained in this proposal to provide important information about the pacing mechanism as well as to understand how dysfunction of HCN channels leads to the sick sinus syndrome.