Abstract
It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.
Highlights
It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system
Previous studies indicated that abolishing the cyclic adenosine monophosphate (cAMP) binding capability of the HCN4 cyclic nucleotide-binding domain is associated with embryonic lethality[10,24]
This finding possibly reflects the fact that the activation thresholds of these HCN4 mutants are more negative than the maximum diastolic potential of pacemaker cells, which is essentially as if no cAMP was present in the cell
Summary
The slow (τau1) and fast (τau2) activation time constants representing activation of HCN4 and HCN1 channels, were similar in WT and HCN4FEA cells (Supplementary Data 1b) in the absence of cAMP. HCN4FEA after complete autonomic blockade, indicating that a second, but minor part of HR fluctuations observed in vivo is independent of the ANS and attributable to intrinsic sinus node dysfunction In support of this conclusion, HR fluctuations in in vitro preparations (isolated perfused hearts and biatrial preparations; Supplementary Data 6a, 8a)—in which intrinsically autonomic regulation is lacking—were lower than those observed in vivo for both mouse groups but were still more pronounced in HCN4FEA preparations. Cells from either WT or HCN4FEA mice fired rhythmic, spontaneous pacemaker potentials
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