cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4

Alessandro Porro; Gerhard Thiel; Anna Moroni; Andrea Saponaro

doi:10.3389/fphys.2020.00771

cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4

Front Physiol. 2020 Jul 7:11:771. doi: 10.3389/fphys.2020.00771. eCollection 2020.

Authors

Alessandro Porro¹, Gerhard Thiel², Anna Moroni¹, Andrea Saponaro¹

Affiliations

¹ Department of Biosciences, University of Milan, Milan, Italy.
² Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.

Abstract

Direct regulation of the pacemaker "funny" current (I_f) 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 I_f 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.

Keywords: cyclic AMP; heart rate; hyperpolarization-activated cyclic nucleotide-gated (HCN) channels; regulation; structure; “funny” current.

Publication types

Review