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

Abstract

AimsActivation of the β1-adrenergic receptor and its G protein, Gs, induces cardiac hypertrophy. However, activation of classic Gαs 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 Gs. Recently, we discovered that βγ subunits of Gq 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 ErkThr188 phosphorylation.Methods and resultsβ-Adrenergic receptor activation induced ErkThr188 phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of ErkThr188 phosphorylation-deficient mutants (Erk2T188A 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. ErkThr188 phosphorylation required Gβγ released from Gs 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 Erk2T188S transgenic mice, supporting the physiological relevance of ErkThr188 phosphorylation.ConclusionsActivation of Gs 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. © 2012 The Author.