Differential control of cardiac pacemaker activity by PDE4 subfamily members
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ID: 329131
2026
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Abstract
AIMS: The cAMP-specific phosphodiesterases 4B and 4D (PDE4B and PDE4D) are critical regulators of cardiac excitation-contraction coupling, but their role in controlling heart rate (HR) remains poorly defined. This study aimed to evaluate their respective contributions to cardiac automaticity. METHODS AND RESULTS: PDE4 activity, measured by a radioenzymatic assay, accounted for ∼60% of the total cAMP-hydrolytic activity in the mouse sinoatrial node (SAN). Western blot and in situ RNA fluorescence hybridization (RNAscope) showed that both PDE4B and PDE4D are expressed in the SAN and in isolated pacemaker cardiomyocytes. HR, measured by ECG telemetry, was increased in Pde4b knockout (Pde4b-/-) and Pde4d knockout (Pde4d-/-) mice compared with wild-type (WT) littermates, during both day and night. Upon autonomic nervous system (ANS) blockade, elevated HR persisted in Pde4b-/- but not in Pde4d-/- mice. Consistently, isolated perfused hearts from Pde4b-/- mice beat faster than wild-type littermates, whereas Pde4d-/- did not. Increased automaticity in Pde4b-/- hearts was not accompanied by modified Ca2+ homeostasis in Fluo-4-loaded isolated SAN tissue, either at baseline or during β-adrenergic (β-AR) stimulation with 10 nM isoprenaline (ISO). In contrast, Pde4d-/- SAN challenged with ISO exhibited an increased total sarcoplasmic reticulum (SR) Ca2+ leak and prolonged Ca2+ transients. Patch-clamp recordings revealed an increased action potential firing rate in Pde4b-/- but not in Pde4d-/- pacemaker cardiomyocytes. In Pde4b-/- cells, basal and ISO-stimulated L-type calcium current (ICa,L) densities were not significantly altered, whereas funny current (If) density was increased. Conversely, Pde4d ablation did not alter basal ICa,L nor If. CONCLUSION: These results show that PDE4B controls intrinsic SAN automaticity by regulating the voltage clock through the pacemaker current If, whereas PDE4D regulates the calcium clock via β-AR-induced calcium release through RyR2.
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| Authors | Walma Pereira de Vasconcelos, Pietro Mesirca, Anne Breidenstein, Audrey Varin, Eleonora Torre, Eliane Morais-Pinto, Laetitia Bouchard, Kaouter Bouadjel, Jérôme Leroy, Patrick Lechêne, Florence Lefebvre, Natalie Fournier, Vincent Algalarrondo, Marco Conti, Francesca Rochais, Jean‐Pierre Bénitah, Guillaume Pidoux, Rodolphe Fischmeister, Ana-Maria Gomez, Matteo E Mangoni, Grégoire Vandecasteele, Delphine Mika |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag201
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| URL | |
| Keywords | Keywords not found |
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