Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4
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Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. / Richter, Wito; Day, Peter; Agrawal, Rani; Bruss, Matthew D; Granier, Sébastien; Wang, Yvonne L; Rasmussen, Søren Gøgsig Faarup; Horner, Kathleen; Wang, Ping; Lei, Tao; Patterson, Andrew J; Kobilka, Brian; Conti, Marco.
In: E M B O Journal, Vol. 27, No. 2, 23.01.2008, p. 384-93.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Signaling from beta1- and beta2-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 Gøgsig Faarup
AU - Horner, Kathleen
AU - Wang, Ping
AU - Lei, Tao
AU - Patterson, Andrew J
AU - Kobilka, Brian
AU - Conti, Marco
PY - 2008/1/23
Y1 - 2008/1/23
N2 - Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR 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 beta1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a beta2AR/beta-arrestin/PDE complex reported previously. The beta1AR 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 beta2AR is a prerequisite for the recruitment of a complex consisting of beta-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 beta1- and beta2-adrenoceptor signaling.
AB - Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR 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 beta1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a beta2AR/beta-arrestin/PDE complex reported previously. The beta1AR 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 beta2AR is a prerequisite for the recruitment of a complex consisting of beta-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 beta1- and beta2-adrenoceptor signaling.
KW - Animals
KW - Animals, Newborn
KW - Cell Line
KW - Cells, Cultured
KW - Cyclic AMP
KW - Cyclic Nucleotide Phosphodiesterases, Type 4
KW - Humans
KW - Immunoprecipitation
KW - Mice
KW - Models, Biological
KW - Muscle Cells
KW - Promoter Regions, Genetic
KW - Protein Binding
KW - Protein Isoforms
KW - Receptors, Adrenergic, beta-1
KW - Receptors, Adrenergic, beta-2
KW - Signal Transduction
U2 - 10.1038/sj.emboj.7601968
DO - 10.1038/sj.emboj.7601968
M3 - Journal article
C2 - 18188154
VL - 27
SP - 384
EP - 393
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 2
ER -
ID: 120588652