Key result
PDE4B controls SA node automaticity via the voltage clock while PDE4D regulates the calcium clock.
Why the study?
The role of PDE4B and PDE4D subfamily members in controlling heart rate and cardiac automaticity remains poorly defined.
Does genetic ablation of PDE4B or PDE4D alter cardiac automaticity and heart rate in mice?
Does genetic ablation of PDE4B or PDE4D alter cardiac automaticity and heart rate in mice?
Answers are grounded in this paper and cite their sources.
PDE4B and PDE4D have distinct roles in regulating cardiac pacemaker activity, with PDE4B controlling intrinsic automaticity via the voltage clock and PDE4D regulating the calcium clock during beta-adrenergic stimulation.
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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Vasconcelos et al. (2026) studied Cardiac automaticity. Pde4b and Pde4d knockout vs. Wild-type littermates was evaluated on Heart rate and cardiac automaticity. PDE4B controls intrinsic sinoatrial node automaticity by regulating the voltage clock through the pacemaker current If, whereas PDE4D regulates the calcium clock via beta-adrenergic-induced calcium release.
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