title: Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling.
abstract: β1 and β2 adrenergic receptors (βARs) are highly homologous but fulfill distinct physiological and pathophysiological roles. Here we show that both βAR subtypes activate the cAMP-binding protein Epac1, but they differentially affect its signaling. The distinct effects of βARs on Epac1 downstream effectors, the small G proteins Rap1 and H-Ras, involve different modes of interaction of Epac1 with the scaffolding protein β-arrestin2 and the cAMP-specific phosphodiesterase (PDE) variant PDE4D5. We found that β-arrestin2 acts as a scaffold for Epac1 and is necessary for Epac1 coupling to H-Ras. Accordingly, knockdown of β-arrestin2 prevented Epac1-induced histone deacetylase 4 (HDAC4) nuclear export and cardiac myocyte hypertrophy upon β1AR activation. Moreover, Epac1 competed with PDE4D5 for interaction with β-arrestin2 following β2AR activation. Dissociation of the PDE4D5-β-arrestin2 complex allowed the recruitment of Epac1 to β2AR and induced a switch from β2AR non-hypertrophic signaling to a β1AR-like pro-hypertrophic signaling cascade. These findings have implications for understanding the molecular basis of cardiac myocyte remodeling and other cellular processes in which βAR subtypes exert opposing effects.
authors.affiliation: Inserm, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 04, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Berthouze-Duquesnes
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lucas
authors.forename: Aude
authors.initials: A
authors.lastname: Saulière
authors.forename: Yuan Yan
authors.initials: YY
authors.lastname: Sin
authors.forename: Anne-Coline
authors.initials: AC
authors.lastname: Laurent
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
authors.forename: George
authors.initials: G
authors.lastname: Baillie
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
mesh_terms: D000818:Animals; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D031541:Fluorescence Resonance Energy Transfer; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D060066:Protein Interaction Maps; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D034741:RNA, Small Interfering; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)