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Signaling from β1‐ and β2‐adrenergic receptors is defined by differential interactions with PDE4
Author(s) -
Richter Wito,
Day Peter,
Agrawal Rani,
Bruss Matthew D.,
Granier Sébastien,
Wang Yvonne L.,
Rasmussen Søren G.F.,
Horner Kathleen,
Wang Ping,
Lei Tao,
Patterson Andrew J.,
Kobilka Brian,
Conti Marco
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1046.7
Subject(s) - receptor , agonist , microbiology and biotechnology , signal transduction , arrestin , stimulation , g protein coupled receptor , adrenergic receptor , phosphodiesterase , biology , myocyte , chemistry , endocrinology , biochemistry , enzyme
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. This research was supported by Fondation Leducq and NIH grants HD20788 to M.C. and HL71078‐01 to B.K.