Signaling from beta(1)- and beta(2)-adrenergic receptors is defined by differential interactions with PDE4

• Type of Material: Article
• Authors: Wito Richter, Stanford University; Peter Day, Stanford University; Rani Agrawal, Stanford University; Matthew D. Bruss, Stanford University; Sébastien Granier, Stanford University; Yvonne L. Wang, Stanford University; Søren G. F. Rasmussen, Stanford University; Kathleen Horner, Stanford University; Ping Wang, Stanford University; Tao Lei, Stanford University; Andrew Patterson, Emory University; Brian Kobilka, Stanford University; Marco Conti, Stanford University
• Language: English
• Date: 2008-01-23
• Publisher: EMBO Press
• Publication Version: Final Published Version
• Copyright Statement: © 2008 European Molecular Biology Organization; Some Rights Reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1038/sj.emboj.7601968
• Title of Journal or Parent Work: EMBO Journal
• ISSN: 0261-4189
• Volume: 27
• Issue: 2
• Start Page: 384
• End Page: 393
• Grant/Funding Information: This research was supported by NIH Grants HD20788 to MC and HL71078-01 to BK, a grant from Fondation Leducq, and a fellowship grant from The Lundbeck Foundation to SGFR.
• Keywords: CARDIAC MYOCYTES; beta-adrenergic receptor; HEART; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; cyclic nucleotide phosphodiesterase; PATHWAYS; Cell Biology; Science & Technology; cardiac myocyte; PROTEIN-KINASE-A; COMPONENTS; CAMP-SPECIFIC PHOSPHODIESTERASES; cAMP; PDE
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Obstetrics and Gynecology

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.