How to recruit a GRK

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Science Signaling  08 May 2018:
Vol. 11, Issue 529, eaau0829
DOI: 10.1126/scisignal.aau0829

The dopamine D2 receptor recruits and activates the kinase GRK2 without the need for G protein activation.

G protein–coupled receptors (GPCRs), such as the dopamine D2 receptor (D2R), signal through both G proteins and β-arrestins. Ligand binding to the GPCR activates G proteins and the production of second messengers to transduce signals. The subsequent recruitment and activation of GPCR kinases (GRKs), which phosphorylate serines and threonines of the GPCR, lead to the recruitment of β-arrestins. Desensitization and internalization of the GPCR by β-arrestins enables the engagement of other effectors to mediate G protein–independent signaling. So-called biased ligands favor one pathway over the other; hence, designing drugs accordingly may lead to better therapeutic effects, while avoiding undesirable side effects. Through experiments with mutant D2Rs engineered to favor either G protein– or β-arrestin–mediated signaling and with the β-arrestin–biased D2R ligand UNC9994, Pack et al. found that D2R could recruit GRK2 independently of G protein activation. Treatment of HEK 293 cells with pertussis toxin (PTX), which blocks Gαi proteins from being activated by D2Rs, failed to prevent β-arrestin recruitment to the β-arrestin–biased D2R, whereas inhibiting the kinase activity of GRK2 blocked the recruitment of β-arrestin to all D2Rs. Experiments with fluorescently tagged proteins showed that GRK2 recruitment to the β-arrestin–biased D2R was not blocked by PTX, unlike for the wild-type receptor. Treatment with UNC9994 resulted in the recruitment of more β-arrestin to the β-arrestin–biased mutant D2R than to either wild-type D2R or the G protein–biased receptor. When GRK2 was overexpressed, UNC9994 led to enhanced recruitment of β-arrestin. Together, these data suggest that a β-arrestin–biased ligand can stimulate β-arrestin recruitment to a GPCR independently of G protein activation, potentially disentangling both pathways, which may aid in the development of selective GPCR drugs.

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