GRK-mediated receptor phosphorylation followed by association with β-arrestins has been proposed to be the molecular mechanism involved in the desensitization of G protein-coupled receptors (GPCRs). However, this mechanism does not explain the desensitization of some GPCRs, such as dopamine D₃ receptor (D₃R), which does not undergo GRK-mediated phosphorylation. Loss-of-function approaches and mutants of dopamine D₂ receptor and D₃R, which exhibit different desensitization properties, were used to identify the cellular components and processes responsible for desensitization. D₃R mediated the recruitment of Mdm2 to the cytosol, which resulted in the constitutive ubiquitination of β-arrestin2 in the resting state. Under desensitization conditions, cytosolic Mdm2 returned to the nucleus, resulting in the deubiquitination of cytosolic β-arrestins. Deubiquitinated β-arrestins formed a tight complex with Gβγ, thereby sequestering it, causing interference in D₃R signaling. In conclusion, this study shows that β-arrestins, depending on their ubiquitination status, control the G protein cycling by regulating their interactions with Gβγ. This is a novel mechanism proposed to explain how certain GPCRs can undergo desensitization without receptor phosphorylation.

GRK介导的受体磷酸化继而与β-arrestin缔合已被认为是G蛋白偶联受体（GPCR）脱敏的分子机制。但是，这种机制不能解释某些GPCR的脱敏性，例如不经历GRK介导的磷酸化的多巴胺D ₃受体（D ₃ R）。表现出不同的脱敏特性的功能丧失方法和多巴胺D ₂受体和D ₃ R的突变体被用于鉴定引起脱敏的细胞成分和过程。d ₃R介导Mdm2向细胞质的募集，从而导致处于静止状态的β-arrestin2组成型泛素化。在脱敏条件下，胞质Mdm2返回到细胞核，导致胞质β-arrestins脱泛素。去泛素化的β-arrestins与Gβγ形成紧密的复合物，从而使其螯合，从而干扰D ₃ R信号传导。总之，这项研究表明，β-arrestin依赖于其泛素化状态，通过调节其与Gβγ的相互作用来控制G蛋白的循环。这是一种新颖的机制，旨在解释某些GPCR如何在不进行受体磷酸化的情况下进行脱敏。