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

Nat Commun. 2020 Nov 3;11(1):5555. doi: 10.1038/s41467-020-19304-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Arrhythmias, Cardiac / complications
  • Arrhythmias, Cardiac / pathology
  • Biological Clocks* / drug effects
  • Blood Pressure / drug effects
  • Bradycardia / complications
  • Bradycardia / pathology
  • Carbachol / pharmacology
  • Cyclic AMP / metabolism*
  • Electrocardiography
  • Female
  • HEK293 Cells
  • Heart / drug effects
  • Heart / physiopathology
  • Heart Rate / drug effects
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
  • Mice, Inbred C57BL
  • Protein Subunits / metabolism
  • Reproducibility of Results
  • Sinoatrial Node / pathology*
  • Sinoatrial Node / physiopathology
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiopathology

Substances

  • Hcn4 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Protein Subunits
  • Carbachol
  • Cyclic AMP