Reorganized PKA-AKAP associations in the failing human heart

Thin Thin Aye, Siddarth Soni, Toon A.B. van Veen, Marcel A.G. van der Heyden, Salvatore Cappadona, Andras Varro, Roel A. de Weger, Nicolaas de Jonge, Marc A. Vos, Albert J.R. Heck, Arjen Scholten

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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".

Original languageEnglish
Pages (from-to)511-518
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume52
Issue number2
DOIs
Publication statusPublished - Feb 1 2012

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Keywords

  • AKAP
  • Chemical proteomics
  • Cyclic nucleotides
  • Heart failure
  • Label-free quantitation
  • Novel therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Aye, T. T., Soni, S., van Veen, T. A. B., van der Heyden, M. A. G., Cappadona, S., Varro, A., de Weger, R. A., de Jonge, N., Vos, M. A., Heck, A. J. R., & Scholten, A. (2012). Reorganized PKA-AKAP associations in the failing human heart. Journal of Molecular and Cellular Cardiology, 52(2), 511-518. https://doi.org/10.1016/j.yjmcc.2011.06.003