Editors' ChoicePharmacology

New connections: Understanding GRK2 signaling to treat disease

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Science Signaling  22 Mar 2016:
Vol. 9, Issue 420, pp. ec69
DOI: 10.1126/scisignal.aaf6651

GRK2 [G protein–coupled receptor (GPCR) kinase 2] can inhibit GPCR signaling through its kinase activity or by uncoupling GPCRs from downstream effectors. A paper in this week’s issue of Science Signaling shows how understanding an in vitro property of a domain in GRK2 could be translated into a treatment that prevents cardiac hypertrophy and heart failure. Untreated high blood pressure leads to cardiac hypertrophy, so that the heart can deal with increased load, but eventually this can lead to heart failure. In vitro, the RGS domain of GRK2 inhibits Gαq, a G protein that promotes cardiac hypertrophy in response to pressure overload. Schumacher et al. generated transgenic mice that overexpressed the RGS domain of GRK2 in a cardiac-specific fashion. After a surgical manipulation to induce pressure overload that can lead to heart failure, the transgenic mice developed less cardiac hypertrophy and retained greater cardiac function than their nontransgenic counterparts. Thus, targeting a peptide encompassing the RGS domain of GRK2 to the heart or a small molecule that mimics the effect of this domain on Gαq could suppress hypertrophic signaling and prevent heart failure. GRK2 may also be a useful molecular target for treating obesity; in this case, it is by inhibition of the kinase activity of GRK2, as reported in a paper published in Science Signaling in 2015. Obesity is associated with the development of insulin resistance, type 2 diabetes, and hepatic steatosis (the accumulation of fat in the liver). In addition to decreasing insulin sensitivity, GRK2 inhibits signaling through β-adrenergic GPCRs, thereby suppressing lipolysis in white adipose tissue and energy burning in brown adipose tissue. To assess the effect of targeting GRK2 in obesity-associated metabolic disorders, Vila-Bedmar et al. genetically ablated GRK2 in adult mice after they had become obese and developed insulin resistance by eating a high-fat diet. These mice did not gain more weight or develop hepatic steatosis on the high-fat diet and showed improvement in various metabolic parameters, including insulin sensitivity. These papers show that application of our understanding of the effects of GRK2 signaling in vitro, in cells, and in organisms could result in novel therapeutic strategies.

S. M. Schumacher, E. Gao, M. Cohen, M. Lieu, J. K. Chuprun, W. J. Koch, A peptide of the RGS domain of GRK2 binds and inhibits Gαq to suppress pathological cardiac hypertrophy and dysfunction. Sci. Signal. 9, ra30 (2016). [Abstract]

R. Vila-Bedmar, M. Cruces-Sande, E. Lucas, H. L. D. M. Willemen, C. J. Heijnen, A. Kavelaars, F. Mayor Jr., C. Murga, Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2. Sci. Signal. 8, ra73 (2015). [Abstract]

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