title: β-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gβγ/Erk-dependent pathway.
abstract: OBJECTIVE
  Activation of the β(1)-adrenergic receptor and its G protein, G(s), induces cardiac hypertrophy. However, activation of classic Gα(s) effectors, adenylyl cyclases (AC) and protein kinase A, is not sufficient for induction of hypertrophy, which suggests the involvement of additional pathway(s) activated by G(s). Recently, we discovered that βγ subunits of G(q) induce phosphorylation of the extracellular regulated kinases 1 and 2 (Erk1/2) at threonine188 and thereby induce hypertrophy. Here we investigated whether β-adrenergic receptors might also induce cardiac hypertrophy via Erk(Thr188) phosphorylation.
  
  
  RESULTS
  β-Adrenergic receptor activation induced Erk(Thr188) phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of Erk(Thr188) phosphorylation-deficient mutants (Erk2(T188A) and Erk2(T188S)) significantly attenuated β-adrenergic cardiomyocyte hypertrophy in vitro. Erk activity was stimulated by both isoproterenol and the direct AC activator forskolin, but only isoproterenol induced Erk(Thr188) phosphorylation. Erk(Thr188) phosphorylation required Gβγ released from G(s) and was prevented by Gβγ inhibition. Similarly, isoproterenol, but not forskolin, induced nuclear accumulation of Erk and cardiomyocyte hypertrophy. Long-term application of isoproterenol in mice caused left ventricular hypertrophy and cardiac remodelling, and this was reduced in Erk2(T188S) transgenic mice, supporting the physiological relevance of Erk(Thr188) phosphorylation.
  
  
  CONCLUSIONS
  Activation of G(s) by β-adrenergic receptors leads to (i) canonical Erk1/2 activation via AC, and (ii) release of Gβγ, which then associates with activated Erk1/2 and induces Erk(Thr188) phosphorylation, causing nuclear accumulation of Erk and ultimately cardiomyocyte hypertrophy. These findings reveal a new pathway critically involved in β-adrenergically mediated cardiac hypertrophy and may yield new therapeutic strategies against hypertrophic remodelling.
authors: Institute of Pharmacology and Toxicology,  University of Würzburg, Versbacher Strasse 9, 97078 Würzburg,  Germany.
authors: Marie
authors: M
authors: Vidal
authors: Thomas
authors: T
authors: Wieland
authors: Martin J
authors: MJ
authors: Lohse
authors: Kristina
authors: K
authors: Lorenz
mesh_terms: D000318:Adrenergic beta-Agonists; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020962:Heterotrimeric GTP-Binding Proteins; D007545:Isoproterenol