title: PDE4B mediates local feedback regulation of β₁-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes.
abstract: Multiple cAMP phosphodiesterase (PDE) isoforms play divergent roles in cardiac homeostasis but the molecular basis for their non-redundant function remains poorly understood. Here, we report a novel role for the PDE4B isoform in β-adrenergic (βAR) signaling in the heart. Genetic ablation of PDE4B disrupted βAR-induced cAMP transients, as measured by FRET sensors, at the sarcolemma but not in the bulk cytosol of cardiomyocytes. This effect was further restricted to a subsarcolemmal compartment because PDE4B regulates β1AR-, but not β2AR- or PGE2-induced responses. The spatially restricted function of PDE4B was confirmed by its selective effects on PKA-mediated phosphorylation patterns. PDE4B limited the PKA-mediated phosphorylation of key players in excitation-contraction coupling that reside in the sarcolemmal compartment, including L-type Ca(2+) channels and ryanodine receptors, but not phosphorylation of distal cytosolic proteins. β1AR- but not β2AR-ligation induced PKA-dependent activation of PDE4B and interruption of this negative feedback with PKA inhibitors increased sarcolemmal cAMP. Thus, PDE4B mediates a crucial PKA-dependent feedback that controls β1AR-dependent cAMP signals in a restricted subsarcolemmal domain. Disruption of this feedback augments local cAMP/PKA signals, leading to an increased intracellular Ca(2+) level and contraction rate.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Mika
authors.forename: Wito
authors.initials: W
authors.lastname: Richter
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Westenbroek
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology*; D004789:Enzyme Activation; D025461:Feedback, Physiological; D007093:Imidazoles / Q000494:pharmacology; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000201:enzymology*; D015290:Second Messenger Systems
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D007093:Imidazoles; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D019837:Ryanodine Receptor Calcium Release Channel; C049763:CGP 20712A; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse; D002118:Calcium
keywords: Cardiac myocytes; Compartmentalization; Cyclic nucleotide phosphodiesterase; PDE; cAMP; β-adrenergic receptors