Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling

Cell Signal. 2013 Apr;25(4):970-80. doi: 10.1016/j.cellsig.2012.12.007. Epub 2012 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / antagonists & inhibitors
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cells, Cultured
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Fluorescence Resonance Energy Transfer
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Protein Interaction Maps
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Signal Transduction
  • beta-Arrestins


  • Arrestins
  • Guanine Nucleotide Exchange Factors
  • RAPGEF3 protein, human
  • RNA, Small Interfering
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • beta-Arrestins
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)