title: A CaMKII/PDE4D negative feedback regulates cAMP signaling.
abstract: cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca(2+) handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca(2+)/CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca(2+)/CaMKII signaling.
authors: Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA 94143.
authors: Delphine
authors: D
authors: Mika
authors: Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA 94143.
authors: Wito
authors: W
authors: Richter
authors: Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA 94143 ContiM@obgyn.ucsf.edu.
authors: Marco
authors: M
authors: Conti
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects / Q000378:metabolism*; D005246:Feedback; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: CaMKII; PDE; cAMP; cyclic nucleotide phosphodiesterase; β-adrenergic signaling
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