title: Reorganized PKA-AKAP associations in the failing human heart.
abstract: Here we reveal that the characterization of large-scale re-arrangements of signaling scaffolds induced by heart failure can serve as a novel concept to identify more specific therapeutic targets. In the mammalian heart, the cAMP pathway, with the cAMP-dependent protein kinase (PKA) in a central role, acts directly downstream of adrenergic receptors to mediate cardiac contractility and rhythm. Heart failure, characterized by severe alterations in adrenergic stimulation is, amongst other interventions, often treated with β-blockers. Contrasting results, however, have shown both beneficial and detrimental effects of decreased cAMP levels in failing hearts. We hypothesize that the origin of this behavior lies in the complex spatiotemporal organization of the regulatory subunit of PKA (PKA-R), which associates tightly with various A-kinase anchoring proteins (AKAPs) to specifically localize PKA's activity. Using chemical proteomics directly applied to human patient and control heart tissue we demonstrate that the association profile of PKA-R with several AKAPs is severely altered in the failing heart, for instance effecting the interaction between PKA and the novel AKAP SPHKAP was 6-fold upregulated upon failing heart conditions. Also a significant increase in captured cGMP-dependent protein kinase (PKG) and phosphodiesterase 2 (PDE2) was observed. The observed altered profiles can already explain many aspects of the aberrant cAMP-response in the failing human heart, validating that this dataset may provide a resource for several novel, more specific, treatment options. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
authors.forename: Thin-Thin
authors.initials: TT
authors.lastname: Aye
authors.forename: Siddarth
authors.initials: S
authors.lastname: Soni
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cappadona
authors.forename: Andras
authors.initials: A
authors.lastname: Varro
authors.forename: Roel A
authors.initials: RA
authors.lastname: de Weger
authors.forename: Nicolaas
authors.initials: N
authors.lastname: de Jonge
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.forename: Arjen
authors.initials: A
authors.lastname: Scholten
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D054758:A Kinase Anchor Proteins; D020543:Proteome; D017868:Cyclic AMP-Dependent Protein Kinases