LAUSR

An accessory protein suppresses β-arrestin–dependent signaling and constitutive activity of the ghrelin receptor. Skewing signaling with an accessory protein Ghrelin is a peptide that is secreted by the stomach during fasting to promote food intake. The accessory protein MRAP2 interacts with the ghrelin receptor GHSR1a and is important for the orexigenic effects of ghrelin. Rouault et al. found that MRAP2 promoted biased signaling downstream of ghrelin-mediated activation of GHSR1a by inhibiting β-arrestin recruitment to the receptor and potentiating Gαq/11-dependent signaling. Furthermore, MRAP2 suppressed ligand-independent activity of GHSR1a, which is naturally high. These results show that accessory proteins can bias GPCR signaling and, for GHSR1a, limit its constitutive activity. Ghrelin is a hormone secreted by the stomach during fasting periods and acts through its receptor, the growth hormone secretagogue 1a (GHSR1a), to promote food intake and prevent hypoglycemia. As such, GHSR1a is an important regulator of energy and glucose homeostasis and a target for the treatment of obesity. Here, we showed that the accessory protein MRAP2 altered GHSR1a signaling by inhibiting its constitutive activity, as well as by enhancing its G protein–dependent signaling and blocking the recruitment and signaling of β-arrestin in response to ghrelin. In addition, the effects of MRAP2 on the Gαq and β-arrestin pathways were independent and involved distinct regions of MRAP2. These findings may have implications for the regulation of ghrelin function in vivo and the role of MRAP2 in energy homeostasis. They also show that accessory proteins can bias signaling downstream of GPCRs in response to their endogenous agonist.