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.

中文翻译：

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GPCR辅助蛋白MRAP2调节生长素释放肽受体GHSR1a的偏向信号传导和组成性活性。

Ghrelin是一种在禁食期间由胃分泌的激素，并通过其受体即生长激素促分泌素1a（GHSR1a）起作用，以促进食物摄入并预防低血糖症。因此，GHSR1a是能量和葡萄糖稳态的重要调节剂，并且是肥胖症治疗的靶标。在这里，我们表明辅助蛋白MRAP2通过抑制其组成活性以及增强其G蛋白依赖性信号传导并阻断对ghrelin的β-arrestin募集和信号传导，从而改变了GHSR1a信号传导。此外，MRAP2对Gαq和β-arrestin途径的影响是独立的，并且涉及MRAP2的不同区域。这些发现可能对体内ghrelin功能的调节以及MRAP2在能量稳态中的作用有关。