Journal Article

DZNE-2026-00021

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png L-Type Cav1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines.

Torre, E. ; Faure, M. ; Bidaud, I. ; Baudot, M. ; Gaillardon, M. ; Pereira de Vasconcelos, W. ; Laarioui, S. ; Talssi, L. ; Engeland, B.DZNE* ; Reiken, S. ; Saponaro, A. ; Chen, B.-X. ; Moroni, A. ; D'Souza, A. ; Isbrandt, D.DZNE* ; Marks, A. R. ; Marx, S. O. ; Mesirca, P. ; Mangoni, M. E.

2026
Assoc. New York, NY

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Please use a persistent id in citations: doi:10.1161/CIRCRESAHA.125.327497

Abstract: The ionic mechanism by which catecholamines increase the heart rate is incompletely understood. In this study, we have assessed the roles of sinoatrial node L-type Cav1.3 (α1D) Ca2+ channels, phosphorylation of L-type channel regulatory partner protein Rad (Ras-related RGK GTP-binding protein), and cAMP-dependent regulation of hyperpolarization-activated HCN (hyperpolarization-activated cyclic nucleotide-gated) channels.We studied β-adrenergic regulation of heart rate and sinoatrial pacemaker activity in mice lacking Cav1.3 channels and in mice expressing dihydropyridine-insensitive L-type Cav1.2 channels alone or concomitantly expressing cAMP-insensitive HCN4 subunits in a heart-specific and time-controlled manner. We also studied the chronotropic response to sympathomimetics of sinoatrial pacemaker myocytes under conditions of specific inhibition of cAMP-dependent regulation of HCN4 by the cyclic dinucleotide cyclic di-(3',5')-GMP and ablation of PKA (protein kinase A)-dependent phosphorylation of Rad.Mutant mice with knockout of Cav1.3 and cAMP-insensitive HCN4 subunits in the heart lacked diurnal variation in heart rate and failed to increase their heart rate after administration of catecholamines or during physical activity. Selective pharmacological inhibition of Cav1.3 prevented the enhancement of pacemaker activity by sympathomimetics or by direct activation of adenylate cyclase, as well as by phosphodiesterase inhibitors, when cAMP-dependent regulation of HCN was simultaneously silenced. Upregulation of Cav1.3 and HCN-mediated funny current (If) accounted for the total change in diastolic current on activation of β-adrenoceptors, explaining the loss of chronotropic effect of catecholamines. Preventing PKA phosphorylation of Rad abrogated the chronotropic response to sympathomimetics of intact hearts under HCN blockade, or in pacemaker myocytes on preventing cAMP-dependent regulation of HCN4, respectively.PKA phosphorylation of Rad, which disinhibits Cav1.3 channels and cAMP-dependent activation of HCN channels, are key effectors in β-adrenergic regulation of cardiac pacemaker activity and can sustain positive chronotropic effects independently. These findings on Rad-mediated regulation of Cav1.3 and HCN channels unravel the ionic mechanisms underlying the catecholaminergic acceleration of the heart rate.

Keyword(s): Animals (MeSH) ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: metabolism (MeSH) ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: genetics (MeSH) ; Heart Rate: drug effects (MeSH) ; Heart Rate: physiology (MeSH) ; Mice (MeSH) ; Calcium Channels, L-Type: genetics (MeSH) ; Calcium Channels, L-Type: metabolism (MeSH) ; Calcium Channels, L-Type: deficiency (MeSH) ; Calcium Channels, L-Type: physiology (MeSH) ; Phosphorylation (MeSH) ; Catecholamines: pharmacology (MeSH) ; Catecholamines: metabolism (MeSH) ; Sinoatrial Node: drug effects (MeSH) ; Sinoatrial Node: metabolism (MeSH) ; Sinoatrial Node: physiology (MeSH) ; Sinoatrial Node: cytology (MeSH) ; Mice, Knockout (MeSH) ; Cyclic AMP-Dependent Protein Kinases: metabolism (MeSH) ; Cyclic AMP: metabolism (MeSH) ; Myocytes, Cardiac: drug effects (MeSH) ; Myocytes, Cardiac: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Male (MeSH) ; Muscle Proteins: metabolism (MeSH) ; Adrenergic beta-Agonists: pharmacology (MeSH) ; ras Proteins (MeSH) ; catecholamines ; heart rate ; phosphorylation ; sinoatrial node ; sympathomimetics ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Calcium Channels, L-Type ; Catecholamines ; Cyclic AMP-Dependent Protein Kinases ; Cyclic AMP ; Hcn4 protein, mouse ; Rrad protein, mouse ; Muscle Proteins ; Adrenergic beta-Agonists ; ras Proteins

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Contributing Institute(s):

1. Experimental Neurophysiology (AG Isbrandt)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; Allianz-Lizenz ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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