Drug discovery efforts targeting G protein–coupled receptors (GPCRs) have succeeded in developing multiple medications for treating various human diseases including cancer, metabolic disorders, and inflammatory disorders. These medications are broadly classified as either agonists or antagonists that respectively promote or inhibit receptor activation by endogenous stimuli. However, there has been a growing appreciation that GPCR biased signaling between G protein- and β-arrestin-dependent signaling in particular is a promising method for improving drug efficacy and therapy. Orexin receptor 1 (OX1R), a member of the GPCRs, is an important drug target in the central nervous system. In this study, we identified a novel regulatory phosphorylation site (Ser-262) on OX1R that abolished its capability to interact with GRK2, but did not affect its interaction with G proteins, GRK5, or β-arrestin1/2 activation, indicating that Ser-262 is a key amino acid for OX1R internalization that contributes to induction of GRK2-dependent biased signaling via orexin A. Our findings could potentially lead to the development of new drug targets for the prevention and treatment of insomnia, narcolepsy, and substance abuse, with fewer side effects than existing therapies.

针对 G 蛋白偶联受体 (GPCR) 的药物发现工作已成功开发出多种药物，用于治疗各种人类疾病，包括癌症、代谢紊乱和炎症性疾病。这些药物大致分为激动剂或拮抗剂，它们分别通过内源性刺激促进或抑制受体激活。然而，越来越多的人认为 GPCR 偏向于 G 蛋白和 β-抑制蛋白依赖性信号之间的信号是提高药物疗效和治疗的有前途的方法。食欲素受体 1 (OX1R) 是 GPCR 的成员，是中枢神经系统中的重要药物靶点。在这项研究中，我们在 OX1R 上发现了一个新的调节磷酸化位点 (Ser-262)，它消除了其与 GRK2 相互作用的能力，