1. Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling
- Author
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Alexandre Lucas, Aude Saulière, George S. Baillie, Anne-Coline Laurent, Céline Galés, Magali Berthouze-Duquesnes, Yuan Yan Sin, Frank Lezoualc'h, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, and Simon, Marie Francoise
- Subjects
MESH: Signal Transduction ,Scaffold protein ,MESH: Fluorescence Resonance Energy Transfer ,Arrestins ,MESH: Myocytes, Cardiac ,030204 cardiovascular system & hematology ,0302 clinical medicine ,MESH: RNA, Small Interfering ,Fluorescence Resonance Energy Transfer ,Guanine Nucleotide Exchange Factors ,MESH: Guanine Nucleotide Exchange Factors ,Myocytes, Cardiac ,MESH: Animals ,Protein Interaction Maps ,RNA, Small Interfering ,Cells, Cultured ,beta-Arrestins ,MESH: Protein Interaction Maps ,0303 health sciences ,Gene knockdown ,Cardiac myocyte ,Phosphodiesterase ,Cell biology ,Biochemistry ,MESH: HEK293 Cells ,RNA Interference ,Rap1 ,MESH: Arrestins ,MESH: Cyclic Nucleotide Phosphodiesterases, Type 3 ,Signal Transduction ,MESH: Cells, Cultured ,MESH: Rats ,MESH: RNA Interference ,Cardiomegaly ,Small G Protein ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Proto-Oncogene Proteins p21(ras) ,MESH: Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Animals ,Humans ,Nuclear export signal ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,MESH: Humans ,Cell Biology ,HDAC4 ,Cyclic Nucleotide Phosphodiesterases, Type 3 ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Rats ,HEK293 Cells ,Receptors, Adrenergic, beta-2 ,MESH: Receptors, Adrenergic, beta-1 ,Receptors, Adrenergic, beta-1 ,MESH: Cardiomegaly ,MESH: Receptors, Adrenergic, beta-2 - Abstract
International audience; 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.
- Published
- 2013