Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4

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

SN - 0261-4189

VL - 27

SP - 384

EP - 393

JO - E M B O Journal

JF - E M B O Journal

IS - 2

ER -