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

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.

cAMP-Dependent Signaling Restores AP Firing in Dormant SA Node Cells via Enhancement of Surface Membrane Currents and Calcium Coupling

“…That study proposed a novel, microscopic signaling paradigm of SAN operation in which synchronized APs emerge from heterogeneous subcellular subthreshold Ca 2+ signals, resembling multiscale complex processes of impulse generation within clusters of neurons in neuronal networks. Another recent study (Fenske et al, 2020) also detected non-firing cells in mouse SAN and provided evidence that a tonic and mutual interaction process (tonic entrainment) between firing and non-firing cells slows down the overall rhythm of the SAN.…”

“…The results of the present study raise, but do not prove, the possibility of the existence of dormant SANC in vivo; but if this were the case, dynamic recruitment of these cells in vivo would likely depend on cAMP-PKA signaling. In other words, some cells that are embedded in SAN tissue, but do not generate APs all the time (Bychkov et al, 2020;Fenske et al, 2020), may activate to fire APs conditionally, namely in the presence of β-AR stimulation in vivo. Other cells may deactivate upon cholinergic receptor stimulation (Goto et al, 1983;Opthof et al, 1987;Fenske et al, 2020).…”

“…More experimental and numerical studies are needed to clarify the role of non-firing cells in SA node and biochemical (cAMP, PKA, and CaMKII signaling) and biophysical mechanisms of dormant cell transition to AP firing, including initial hyperpolarization. Multi-cellular and multiscale numerical modeling would include dormant cells and test several new hypotheses of SAN operational paradigm that have been proposed but not validated yet, including the ideas of subthreshold signal summation among neighboring cells (Bychkov et al, 2020), stochastic resonance (Clancy and Santana, 2020), percolating criticality (Weiss and Qu, 2020), and cell silencing at lower rates (Fenske et al, 2020).…”

Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome

“…With distinct intrinsic automaticity of each pacemaker cluster, the SAN synchronizes all of them and generates an “integral” rhythm. This rhythm is mainly determined by the cluster that displays the fastest firing rate [ 62 ]. Pacemaker clusters are connected through low resistance gap junctions, and affect each other by local circuit currents, which is known as mutual entrainment [ 63 , 64 ].…”

Implantation of Combined Telemetric ECG and Blood Pressure Transmitters to Determine Spontaneous Baroreflex Sensitivity in Conscious Mice

“…WT animals (C57BL/6J background) and animals of a sick sinus syndrome mouse model displaying increased BRS sensitivity (Hcn4 tm3(Y527F;R669E;T670A)Biel ) 11 (mixed C57BL/6N and 129/SvJ background) were used for this study.…”