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Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function

The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for generating the intrinsic heartbeat. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depen...

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Autores principales: Hennis, Konstantin, Rötzer, René D., Piantoni, Chiara, Biel, Martin, Wahl-Schott, Christian, Fenske, Stefanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191466/
https://www.ncbi.nlm.nih.gov/pubmed/34122140
http://dx.doi.org/10.3389/fphys.2021.669029
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author Hennis, Konstantin
Rötzer, René D.
Piantoni, Chiara
Biel, Martin
Wahl-Schott, Christian
Fenske, Stefanie
author_facet Hennis, Konstantin
Rötzer, René D.
Piantoni, Chiara
Biel, Martin
Wahl-Schott, Christian
Fenske, Stefanie
author_sort Hennis, Konstantin
collection PubMed
description The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for generating the intrinsic heartbeat. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depends on the slow diastolic depolarization (SDD) and determines the intrinsic heart rate (HR). To adapt cardiac output to varying physical demands, HR is regulated by the autonomic nervous system (ANS). The sympathetic and parasympathetic branches of the ANS innervate the SAN and regulate the firing rate of pacemaker cells by accelerating or decelerating SDD–a process well-known as the chronotropic effect. Although this process is of fundamental physiological relevance, it is still incompletely understood how it is mediated at the subcellular level. Over the past 20 years, most of the work to resolve the underlying cellular mechanisms has made use of genetically engineered mouse models. In this review, we focus on the findings from these mouse studies regarding the cellular mechanisms involved in the generation and regulation of the heartbeat, with particular focus on the highly debated role of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 in mediating the chronotropic effect. By focusing on experimental data obtained in mice and humans, but not in other species, we outline how findings obtained in mice relate to human physiology and pathophysiology and provide specific information on how dysfunction or loss of HCN4 channels leads to human SAN disease.
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spelling pubmed-81914662021-06-11 Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function Hennis, Konstantin Rötzer, René D. Piantoni, Chiara Biel, Martin Wahl-Schott, Christian Fenske, Stefanie Front Physiol Physiology The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for generating the intrinsic heartbeat. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depends on the slow diastolic depolarization (SDD) and determines the intrinsic heart rate (HR). To adapt cardiac output to varying physical demands, HR is regulated by the autonomic nervous system (ANS). The sympathetic and parasympathetic branches of the ANS innervate the SAN and regulate the firing rate of pacemaker cells by accelerating or decelerating SDD–a process well-known as the chronotropic effect. Although this process is of fundamental physiological relevance, it is still incompletely understood how it is mediated at the subcellular level. Over the past 20 years, most of the work to resolve the underlying cellular mechanisms has made use of genetically engineered mouse models. In this review, we focus on the findings from these mouse studies regarding the cellular mechanisms involved in the generation and regulation of the heartbeat, with particular focus on the highly debated role of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 in mediating the chronotropic effect. By focusing on experimental data obtained in mice and humans, but not in other species, we outline how findings obtained in mice relate to human physiology and pathophysiology and provide specific information on how dysfunction or loss of HCN4 channels leads to human SAN disease. Frontiers Media S.A. 2021-05-27 /pmc/articles/PMC8191466/ /pubmed/34122140 http://dx.doi.org/10.3389/fphys.2021.669029 Text en Copyright © 2021 Hennis, Rötzer, Piantoni, Biel, Wahl-Schott and Fenske. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Hennis, Konstantin
Rötzer, René D.
Piantoni, Chiara
Biel, Martin
Wahl-Schott, Christian
Fenske, Stefanie
Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function
title Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function
title_full Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function
title_fullStr Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function
title_full_unstemmed Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function
title_short Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function
title_sort speeding up the heart? traditional and new perspectives on hcn4 function
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191466/
https://www.ncbi.nlm.nih.gov/pubmed/34122140
http://dx.doi.org/10.3389/fphys.2021.669029
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