TY - JOUR
T1 - Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4
AU - Richter, Wito
AU - Day, Peter
AU - Agrawal, Rani
AU - Bruss, Matthew D.
AU - Granier, Sébastien
AU - Wang, Yvonne L.
AU - Rasmussen, Søren G.F.
AU - Horner, Kathleen
AU - Wang, Ping
AU - Lei, Tao
AU - Patterson, Andrew J.
AU - Kobilka, Brian
AU - Conti, Marco
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/1/23
Y1 - 2008/1/23
N2 - 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.
AB - 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.
KW - Cardiac myocyte
KW - Cyclic nucleotide phosphodiesterase
KW - PDE
KW - cAMP
KW - β-adrenergic receptor
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U2 - 10.1038/sj.emboj.7601968
DO - 10.1038/sj.emboj.7601968
M3 - Article
C2 - 18188154
AN - SCOPUS:38549107922
VL - 27
SP - 384
EP - 393
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 2
ER -