Compartmentalized phosphodiesterase-2 activity blunts β-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway

Marco Mongillo, Carlo G. Tocchetti, Anna Terrin, Valentina Lissandron, York Fong Cheung, Wolfgang R. Dostmann, Tullio Pozzan, David A Kass, Nazareno Paolocci, Miles D. Houslay, Manuela Zaccolo

Research output: Contribution to journalArticle

Abstract

β-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP] i in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving β3-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by β-adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the β-adrenergic pathway. In this, activation of β3-adrenergic receptors counteracts cAMP generation obtained via stimulation of β12-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.

Original languageEnglish (US)
Pages (from-to)226-234
Number of pages9
JournalCirculation Research
Volume98
Issue number2
DOIs
StatePublished - Feb 2006

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Keywords

  • cAMP
  • Cardiomyocytes
  • Compartmentalization
  • Fluorescence resonance energy transfer
  • PDE2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mongillo, M., Tocchetti, C. G., Terrin, A., Lissandron, V., Cheung, Y. F., Dostmann, W. R., Pozzan, T., Kass, D. A., Paolocci, N., Houslay, M. D., & Zaccolo, M. (2006). Compartmentalized phosphodiesterase-2 activity blunts β-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circulation Research, 98(2), 226-234. https://doi.org/10.1161/01.RES.0000200178.34179.93