Research ArticleGPCR SIGNALING

Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9

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Science Signaling  25 Sep 2018:
Vol. 11, Issue 549, eaat7650
DOI: 10.1126/scisignal.aat7650

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The balancing act of β-arrestins

G protein–coupled receptors (GPCRs) are thought to activate the kinases ERK1/2 through G protein– and β-arrestin–dependent pathways. The relative contribution of each is difficult to assess because β-arrestins prevent G protein coupling by GPCRs (see the Focus by Gurevich and Gurevich). Studies based on CRISPR/Cas9-generated cell lines suggested that β-arrestins are dispensable for ERK1/2 activation. Luttrell et al. compared the effects of siRNA-mediated and CRISPR/Cas9-mediated knockdown of β-arrestins on ERK1/2 activation by several GPCRs in independent clones. Their data showed that signaling rewiring in the CRISPR clones rendered GPCR-dependent ERK1/2 activation more G protein–dependent, which was reversed by reconstitution with β-arrestins. Together, these findings suggest that β-arrestins balance signaling through the different pathways from GPCRs to ERK1/2 and suggest that experiments with deletion of β-arrestins or G proteins should be interpreted with caution.