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β-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gβγ/Erk-dependent pathway

Marie Vidal1, Thomas Wieland, Martin J Lohse

  • 1Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.

Cardiovascular Research
|July 31, 2012
PubMed
Abstract

Insights

Beta-adrenergic receptor activation induces cardiac hypertrophy through a novel pathway involving G protein G(s) and extracellular signal-regulated kinases (Erk). This Erk(Thr188) phosphorylation is critical for hypertrophic remodeling and may offer new therapeutic targets.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Signaling

Background:

  • Beta-1 adrenergic receptor and G(s) protein activation induce cardiac hypertrophy.
  • Canonical G(s) effectors (adenylyl cyclase and protein kinase A) are insufficient for hypertrophy.
  • G(q) protein βγ subunits induce cardiac hypertrophy via extracellular signal-regulated kinases (Erk1/2) phosphorylation at threonine188.

Purpose of the Study:

  • Investigate if β-adrenergic receptors induce cardiac hypertrophy via Erk(Thr188) phosphorylation.
  • Elucidate the signaling pathway linking β-adrenergic receptors to Erk(Thr188) phosphorylation and cardiac hypertrophy.

Main Methods:

  • Utilized mouse hearts and neonatal cardiomyocytes.
  • Employed Erk1/2 inhibition and Erk2(T188A/T188S) phosphorylation-deficient mutants.
  • Administered isoproterenol and forskolin (adenylyl cyclase activator).
  • Assessed Erk(Thr188) phosphorylation, nuclear Erk accumulation, and cardiomyocyte hypertrophy.
  • Investigated the role of Gβγ subunits.
  • Conducted long-term in vivo studies with Erk2(T188S) transgenic mice.

Main Results:

  • β-Adrenergic receptor activation induced Erk(Thr188) phosphorylation in cardiac cells and mouse hearts.
  • Erk1/2 inhibition or Erk2(T188A/T188S) mutants attenuated β-adrenergic cardiomyocyte hypertrophy.
  • Isoproterenol, but not forskolin, induced Erk(Thr188) phosphorylation and nuclear Erk accumulation.
  • Erk(Thr188) phosphorylation required Gβγ released from G(s).
  • Long-term isoproterenol treatment caused cardiac hypertrophy and remodeling in mice, which was reduced in Erk2(T188S) mice.

Conclusions:

  • β-Adrenergic receptor activation of G(s) triggers both canonical Erk1/2 activation via adenylyl cyclase and Gβγ release.
  • Released Gβγ associates with Erk1/2, inducing Erk(Thr188) phosphorylation, nuclear translocation, and cardiomyocyte hypertrophy.
  • This pathway is critical for β-adrenergically mediated cardiac hypertrophy and presents potential therapeutic targets for hypertrophic remodeling.

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