Differential control of cardiac pacemaker activity by PDE4 subfamily members
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 Ca 2+ 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) Ca 2+ leak and prolonged Ca 2+ 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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BibTeX
@article{vasconcelos2026differential,
title = {{Differential control of cardiac pacemaker activity by PDE4 subfamily members}},
author = {Walma Pereira de Vasconcelos and Pietro Mesirca and Anne Breidenstein and Audrey Varin and Eleonora Torre and Eliane Morais-Pinto and Laetitia Bouchard and Kaouter Bouadjel and Jérôme Leroy and Patrick Lechène and Florence Lefebvre and Natalie Fournier and Vincent Algalarrondo and Marco Conti and Francesca Rochais and Jean-Pierre Benitah and Guillaume Pidoux and Rodolphe Fischmeister and Ana-Maria Gomez and Matteo Mangoni and Grégoire Vandecasteele and Delphine Mika},
journal = {Cardiovascular Research},
year = {2026},
month = sep,
doi = {10.1093/cvr/cvag201},
url = {https://hal.science/hal-05755150v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Differential control of cardiac pacemaker activity by PDE4 subfamily members
AU - Walma Pereira de Vasconcelos
AU - Pietro Mesirca
AU - Anne Breidenstein
AU - Audrey Varin
AU - Eleonora Torre
AU - Eliane Morais-Pinto
AU - Laetitia Bouchard
AU - Kaouter Bouadjel
AU - Jérôme Leroy
AU - Patrick Lechène
AU - Florence Lefebvre
AU - Natalie Fournier
AU - Vincent Algalarrondo
AU - Marco Conti
AU - Francesca Rochais
AU - Jean-Pierre Benitah
AU - Guillaume Pidoux
AU - Rodolphe Fischmeister
AU - Ana-Maria Gomez
AU - Matteo Mangoni
AU - Grégoire Vandecasteele
AU - Delphine Mika
PY - 2026
DA - 2026/09/17
JO - Cardiovascular Research
DO - 10.1093/cvr/cvag201
UR - https://hal.science/hal-05755150v1
AB - 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 Ca 2+ 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) Ca 2+ leak and prolonged Ca 2+ 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.
SN - 0008-6363
ER -