Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4

Wito Richter, Peter Day, Rani Agrawal, Matthew D. Bruss, Sébastien Granier, Yvonne L. Wang, Søren G.F. Rasmussen, Kathleen Horner, Ping Wang, Tao Lei, Andrew J. Patterson, Brian Kobilka, Marco Conti

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

β1- and β2-adrenergic receptors (βARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by β1AR but not β2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that β1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a β2AR/β-arrestin/PDE complex reported previously. The β1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the β2AR is a prerequisite for the recruitment of a complex consisting of β-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of β1- and β2-adrenoceptor signaling.

Original languageEnglish (US)
Pages (from-to)384-393
Number of pages10
JournalEMBO Journal
Volume27
Issue number2
DOIs
StatePublished - Jan 23 2008

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Keywords

  • Cardiac myocyte
  • Cyclic nucleotide phosphodiesterase
  • PDE
  • cAMP
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Richter, W., Day, P., Agrawal, R., Bruss, M. D., Granier, S., Wang, Y. L., Rasmussen, S. G. F., Horner, K., Wang, P., Lei, T., Patterson, A. J., Kobilka, B., & Conti, M. (2008). Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4. EMBO Journal, 27(2), 384-393. https://doi.org/10.1038/sj.emboj.7601968