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Author Notes:
E-mail: marco.conti@stanford.edu
These authors contributed equally to this work
Acknowledgements: We are indebted to Mastura Wahedi and Ana Paula Galvao Da Silva for their assistance with animal experiments.
We thank Dr R Lefkowitz for the kind gift of MEFs deficient in β-arrestin 1 and 2 and Dr Chen Yan for providing the PDE3A1-DN adenovirus and anti-PDE3A antibodies.
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Research Funding:
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:
- Science & Technology
- Life Sciences & Biomedicine
- Biochemistry & Molecular Biology
- Cell Biology
- beta-adrenergic receptor
- cAMP
- cardiac myocyte
- cyclic nucleotide phosphodiesterase
- PDE
- CAMP-SPECIFIC PHOSPHODIESTERASES
- PROTEIN-KINASE-A
- CARDIAC MYOCYTES
- PATHWAYS
- HEART
- COMPONENTS
Signaling from beta(1)- and beta(2)-adrenergic receptors is defined by differential interactions with PDE4
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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.
Copyright information:
© 2008 European Molecular Biology Organization | Some Rights Reserved.
This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).
