TY  - JOUR
AU  - Torre, Eleonora
AU  - Faure, Mélanie
AU  - Bidaud, Isabelle
AU  - Baudot, Matthias
AU  - Gaillardon, Marvin
AU  - Pereira de Vasconcelos, Walma
AU  - Laarioui, Sihame
AU  - Talssi, Leïla
AU  - Engeland, Birgit
AU  - Reiken, Steven
AU  - Saponaro, Andrea
AU  - Chen, Bi-Xing
AU  - Moroni, Anna
AU  - D'Souza, Alicia
AU  - Isbrandt, Dirk
AU  - Marks, Andrew R
AU  - Marx, Steven O
AU  - Mesirca, Pietro
AU  - Mangoni, Matteo E
TI  - L-Type Cav1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines.
JO  - Circulation research
VL  - 138
IS  - 1
SN  - 0009-7330
CY  - New York, NY
PB  - Assoc.
M1  - DZNE-2026-00021
SP  - e327497
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: metabolism
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: genetics
KW  - Heart Rate: drug effects
KW  - Heart Rate: physiology
KW  - Mice
KW  - Calcium Channels, L-Type: genetics
KW  - Calcium Channels, L-Type: metabolism
KW  - Calcium Channels, L-Type: deficiency
KW  - Calcium Channels, L-Type: physiology
KW  - Phosphorylation
KW  - Catecholamines: pharmacology
KW  - Catecholamines: metabolism
KW  - Sinoatrial Node: drug effects
KW  - Sinoatrial Node: metabolism
KW  - Sinoatrial Node: physiology
KW  - Sinoatrial Node: cytology
KW  - Mice, Knockout
KW  - Cyclic AMP-Dependent Protein Kinases: metabolism
KW  - Cyclic AMP: metabolism
KW  - Myocytes, Cardiac: drug effects
KW  - Myocytes, Cardiac: metabolism
KW  - Mice, Inbred C57BL
KW  - Male
KW  - Muscle Proteins: metabolism
KW  - Adrenergic beta-Agonists: pharmacology
KW  - ras Proteins
KW  - catecholamines (Other)
KW  - heart rate (Other)
KW  - phosphorylation (Other)
KW  - sinoatrial node (Other)
KW  - sympathomimetics (Other)
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (NLM Chemicals)
KW  - Calcium Channels, L-Type (NLM Chemicals)
KW  - Catecholamines (NLM Chemicals)
KW  - Cyclic AMP-Dependent Protein Kinases (NLM Chemicals)
KW  - Cyclic AMP (NLM Chemicals)
KW  - Hcn4 protein, mouse (NLM Chemicals)
KW  - Rrad protein, mouse (NLM Chemicals)
KW  - Muscle Proteins (NLM Chemicals)
KW  - Adrenergic beta-Agonists (NLM Chemicals)
KW  - ras Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41342134
C2  - pmc:PMC12757128
DO  - DOI:10.1161/CIRCRESAHA.125.327497
UR  - https://pub.dzne.de/record/283125
ER  -