Cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4.

Alessandro Porro,Andrea Saponaro,Gerhard Thiel,Anna Moroni

doi:10.3389/fphys.2020.00771

Abstract

Direct regulation of the pacemaker “funny” current (If) by cyclic AMP (cAMP) underlies heart rate modulation by the autonomic nervous system. At the molecular level, cAMP activates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that drive If in sinoatrial node (SAN) myocytes. Even though HCN channel genes were identified more than 20 years ago, the understanding of how cAMP regulates their gating is still fragmented. Here we summarize present understanding on how the cAMP signal is transmitted from the cytosolic to the transmembrane (TM) domain in HCN4. We further discuss how detailed structural knowledge prompted the development of pharmacological/genetic tools for the control of cAMP regulation in these channels.

Highlights

Automaticity of heartbeat originates in the sinoatrial node (SAN), where specialized cardiomyocytes initiate spontaneous impulses in the absence of external stimuli
If is modulated by the second messenger cyclic AMP, which enhances channel open probability, shifting the voltage-dependency of opening to more positive values and increasing the amount of current at any given voltage (DiFrancesco and Tortora, 1991). This mechanism is of crucial physiological relevance as it contributes to the autonomic regulation of heart rate by adrenaline and acetylcholine, which modulate cAMP concentration of SAN myocytes
It is worth noting that cAMP controls different pathways in SAN myocytes, all converging to the modulation of heart rate (Behar et al, 2016)

Summary

INTRODUCTION

Automaticity of heartbeat originates in the sinoatrial node (SAN), where specialized cardiomyocytes initiate spontaneous impulses in the absence of external stimuli. If is modulated by the second messenger cyclic AMP (cAMP), which enhances channel open probability, shifting the voltage-dependency of opening to more positive values and increasing the amount of current at any given voltage (DiFrancesco and Tortora, 1991). This mechanism is of crucial physiological relevance as it contributes to the autonomic regulation of heart rate by adrenaline and acetylcholine, which modulate cAMP concentration of SAN myocytes. Taking HCN4 as a paradigm, we will further show how the precise knowledge of this mechanism leads to the discovery of modalities to interfere with it, paving the way to future therapeutic and pharmacological interventions for the control of heart rate

INSIGHT INTO cAMP REGULATION COMES FROM THE STRUCTURES OF HCN CHANNELS

THE CONFORMATIONAL CHANGES INDUCED BY cAMP IN THE CNBD

TRANSMISSION OF cAMP EFFECT

THE TRANSMISSION OF THE cAMP EFFECT TO THE TM DOMAIN