Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3728643

In Collections

This item can be found in the following collections:

Subramaniam, G.; Schleicher, K.; Kovanich, D.; Zerio, A.; Folkmanaite, M.; Chao, Y.C.; ... ; Zaccolo, M. (2023)

Integrated proteomics unveils nuclear PDE3A2 as a regulator of cardiac myocyte hypertrophy

Article / Letter to editor
BACKGROUND: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac beta-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing.METHODS: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with beta-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans.RESULTS: We demonstrate the validity of the...Show moreBACKGROUND: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac beta-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing.METHODS: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with beta-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans.RESULTS: We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth.CONCLUSIONS: We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors.Show less
adrenergic agents
hypertrophy
phosphoric diester hydrolases
protein isoforms
rodentia
All authors
Subramaniam, G.; Schleicher, K.; Kovanich, D.; Zerio, A.; Folkmanaite, M.; Chao, Y.C.; Surdo, N.C.; Koschinski, A.; Hu, J.S.; Scholten, A.; Heck, A.J.R.; Ercu, M.; Sholokh, A.; Park, K.C.; Klussmann, E.; Meraviglia, V.; Bellin, M.; Zanivan, S.; Hester, S.; Mohammed, S.; Zaccolo, M.
Date
2023-03-31
Journal
Circulation Research
Volume
132
Issue
7
Pages
828 - 848
DOI
doi:10.1161/CIRCRESAHA.122.321448
Link
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.321448