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@ARTICLE{Torre:283125,
      author       = {Torre, Eleonora and Faure, Mélanie and Bidaud, Isabelle
                      and Baudot, Matthias and Gaillardon, Marvin and Pereira de
                      Vasconcelos, Walma and Laarioui, Sihame and Talssi, Leïla
                      and Engeland, Birgit and Reiken, Steven and Saponaro, Andrea
                      and Chen, Bi-Xing and Moroni, Anna and D'Souza, Alicia and
                      Isbrandt, Dirk and Marks, Andrew R and Marx, Steven O and
                      Mesirca, Pietro and Mangoni, Matteo E},
      title        = {{L}-{T}ype {C}av1.3 and {HCN} {C}hannels {M}ediate {H}eart
                      {R}ate {A}cceleration by {C}atecholamines.},
      journal      = {Circulation research},
      volume       = {138},
      number       = {1},
      issn         = {0009-7330},
      address      = {New York, NY},
      publisher    = {Assoc.},
      reportid     = {DZNE-2026-00021},
      pages        = {e327497},
      year         = {2026},
      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.},
      keywords     = {Animals / Hyperpolarization-Activated Cyclic
                      Nucleotide-Gated Channels: metabolism /
                      Hyperpolarization-Activated Cyclic Nucleotide-Gated
                      Channels: genetics / Heart Rate: drug effects / Heart Rate:
                      physiology / Mice / Calcium Channels, L-Type: genetics /
                      Calcium Channels, L-Type: metabolism / Calcium Channels,
                      L-Type: deficiency / Calcium Channels, L-Type: physiology /
                      Phosphorylation / Catecholamines: pharmacology /
                      Catecholamines: metabolism / Sinoatrial Node: drug effects /
                      Sinoatrial Node: metabolism / Sinoatrial Node: physiology /
                      Sinoatrial Node: cytology / Mice, Knockout / Cyclic
                      AMP-Dependent Protein Kinases: metabolism / Cyclic AMP:
                      metabolism / Myocytes, Cardiac: drug effects / Myocytes,
                      Cardiac: metabolism / Mice, Inbred C57BL / Male / Muscle
                      Proteins: metabolism / Adrenergic beta-Agonists:
                      pharmacology / ras Proteins / catecholamines (Other) / heart
                      rate (Other) / phosphorylation (Other) / sinoatrial node
                      (Other) / sympathomimetics (Other) /
                      Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
                      (NLM Chemicals) / Calcium Channels, L-Type (NLM Chemicals) /
                      Catecholamines (NLM Chemicals) / Cyclic AMP-Dependent
                      Protein Kinases (NLM Chemicals) / Cyclic AMP (NLM Chemicals)
                      / Hcn4 protein, mouse (NLM Chemicals) / Rrad protein, mouse
                      (NLM Chemicals) / Muscle Proteins (NLM Chemicals) /
                      Adrenergic beta-Agonists (NLM Chemicals) / ras Proteins (NLM
                      Chemicals)},
      cin          = {AG Isbrandt},
      ddc          = {610},
      cid          = {I:(DE-2719)1011003},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41342134},
      pmc          = {pmc:PMC12757128},
      doi          = {10.1161/CIRCRESAHA.125.327497},
      url          = {https://pub.dzne.de/record/283125},
}