We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Signaling from β<sub>1</sub>- and β<sub>2</sub>-adrenergic receptors is defined by differential interactions with PDE4.
- Authors
Richter, Wito; Day, Peter; Agrawal, Rani; Bruss, Matthew D; Granier, Sébastien; Wang, Yvonne L.; Rasmussen, Søren G. F.; Horner, Kathleen; Ping Wang; Tao Lei; Patterson, Andrew J.; Kobilka, Brian; Conti, Marco
- 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.
- Publication
EMBO Journal, 2008, Vol 27, Issue 2, p384
- ISSN
0261-4189
- Publication type
Academic Journal
- DOI
10.1038/sj.emboj.7601968