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000283125 0247_ $$2doi$$a10.1161/CIRCRESAHA.125.327497
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000283125 037__ $$aDZNE-2026-00021
000283125 041__ $$aEnglish
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000283125 1001_ $$00000-0003-1822-8495$$aTorre, Eleonora$$b0
000283125 245__ $$aL-Type Cav1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines.
000283125 260__ $$aNew York, NY$$bAssoc.$$c2026
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000283125 520__ $$aThe 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.
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000283125 650_7 $$2Other$$acatecholamines
000283125 650_7 $$2Other$$aheart rate
000283125 650_7 $$2Other$$aphosphorylation
000283125 650_7 $$2Other$$asinoatrial node
000283125 650_7 $$2Other$$asympathomimetics
000283125 650_7 $$2NLM Chemicals$$aHyperpolarization-Activated Cyclic Nucleotide-Gated Channels
000283125 650_7 $$2NLM Chemicals$$aCalcium Channels, L-Type
000283125 650_7 $$2NLM Chemicals$$aCatecholamines
000283125 650_7 $$0EC 2.7.11.11$$2NLM Chemicals$$aCyclic AMP-Dependent Protein Kinases
000283125 650_7 $$0E0399OZS9N$$2NLM Chemicals$$aCyclic AMP
000283125 650_7 $$2NLM Chemicals$$aHcn4 protein, mouse
000283125 650_7 $$2NLM Chemicals$$aRrad protein, mouse
000283125 650_7 $$2NLM Chemicals$$aMuscle Proteins
000283125 650_7 $$2NLM Chemicals$$aAdrenergic beta-Agonists
000283125 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aras Proteins
000283125 650_2 $$2MeSH$$aAnimals
000283125 650_2 $$2MeSH$$aHyperpolarization-Activated Cyclic Nucleotide-Gated Channels: metabolism
000283125 650_2 $$2MeSH$$aHyperpolarization-Activated Cyclic Nucleotide-Gated Channels: genetics
000283125 650_2 $$2MeSH$$aHeart Rate: drug effects
000283125 650_2 $$2MeSH$$aHeart Rate: physiology
000283125 650_2 $$2MeSH$$aMice
000283125 650_2 $$2MeSH$$aCalcium Channels, L-Type: genetics
000283125 650_2 $$2MeSH$$aCalcium Channels, L-Type: metabolism
000283125 650_2 $$2MeSH$$aCalcium Channels, L-Type: deficiency
000283125 650_2 $$2MeSH$$aCalcium Channels, L-Type: physiology
000283125 650_2 $$2MeSH$$aPhosphorylation
000283125 650_2 $$2MeSH$$aCatecholamines: pharmacology
000283125 650_2 $$2MeSH$$aCatecholamines: metabolism
000283125 650_2 $$2MeSH$$aSinoatrial Node: drug effects
000283125 650_2 $$2MeSH$$aSinoatrial Node: metabolism
000283125 650_2 $$2MeSH$$aSinoatrial Node: physiology
000283125 650_2 $$2MeSH$$aSinoatrial Node: cytology
000283125 650_2 $$2MeSH$$aMice, Knockout
000283125 650_2 $$2MeSH$$aCyclic AMP-Dependent Protein Kinases: metabolism
000283125 650_2 $$2MeSH$$aCyclic AMP: metabolism
000283125 650_2 $$2MeSH$$aMyocytes, Cardiac: drug effects
000283125 650_2 $$2MeSH$$aMyocytes, Cardiac: metabolism
000283125 650_2 $$2MeSH$$aMice, Inbred C57BL
000283125 650_2 $$2MeSH$$aMale
000283125 650_2 $$2MeSH$$aMuscle Proteins: metabolism
000283125 650_2 $$2MeSH$$aAdrenergic beta-Agonists: pharmacology
000283125 650_2 $$2MeSH$$aras Proteins
000283125 7001_ $$aFaure, Mélanie$$b1
000283125 7001_ $$00000-0002-1812-1447$$aBidaud, Isabelle$$b2
000283125 7001_ $$00000-0002-8725-3048$$aBaudot, Matthias$$b3
000283125 7001_ $$aGaillardon, Marvin$$b4
000283125 7001_ $$00009-0000-2471-8445$$aPereira de Vasconcelos, Walma$$b5
000283125 7001_ $$00009-0009-4852-371X$$aLaarioui, Sihame$$b6
000283125 7001_ $$aTalssi, Leïla$$b7
000283125 7001_ $$0P:(DE-2719)2810970$$aEngeland, Birgit$$b8
000283125 7001_ $$00000-0002-5807-3574$$aReiken, Steven$$b9
000283125 7001_ $$00000-0001-5035-5174$$aSaponaro, Andrea$$b10
000283125 7001_ $$aChen, Bi-Xing$$b11
000283125 7001_ $$00000-0002-1860-406X$$aMoroni, Anna$$b12
000283125 7001_ $$00000-0002-9700-5523$$aD'Souza, Alicia$$b13
000283125 7001_ $$0P:(DE-2719)2810976$$aIsbrandt, Dirk$$b14
000283125 7001_ $$00000-0002-8057-1502$$aMarks, Andrew R$$b15
000283125 7001_ $$00000-0002-0577-6030$$aMarx, Steven O$$b16
000283125 7001_ $$00000-0002-9538-3096$$aMesirca, Pietro$$b17
000283125 7001_ $$00000-0002-8892-3373$$aMangoni, Matteo E$$b18
000283125 773__ $$0PERI:(DE-600)1467838-X$$a10.1161/CIRCRESAHA.125.327497$$gVol. 138, no. 1$$n1$$pe327497$$tCirculation research$$v138$$x0009-7330$$y2026
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