Article
- The EMBO Journal (2008) 27, 384 - 393
- doi:10.1038/sj.emboj.7601968
Published online: 10 January 2008
Subject Category:
Signaling from 
1- and 2-adrenergic receptors is defined by differential interactions with PDE4EMBO Open
Wito Richter1,4, Peter Day2,4, Rani Agrawal3, Matthew D Bruss1, Sébastien Granier2, Yvonne L Wang1, Søren G F Rasmussen2, Kathleen Horner1, Ping Wang1, Tao Lei1, Andrew J Patterson3, Brian Kobilka2 and Marco Conti1
- Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
Correspondence to:
Marco Conti, Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building, Room S301, Stanford, CA 94305-5317, USA. Tel.: +1 650 725 2452; Fax: +1 650 725 7102; E-mail: marco.conti@stanford.edu
4These authors contributed equally to this work
Received 29 June 2007; Accepted 3 December 2007
Abstract
1- and 2-adrenergic receptors (ARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by 1AR but not 2AR 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 1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a 2AR/-arrestin/PDE complex reported previously. The 1AR 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 2AR is a prerequisite for the recruitment of a complex consisting of -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 1- and 2-adrenoceptor signaling.
Keywords:
- -adrenergic receptor,
- cAMP,
- cardiac myocyte,
- cyclic nucleotide phosphodiesterase,
- PDE
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