Desensitization of G protein–coupled receptors (GPCRs) refers to a rapid attenuation of responsiveness that occurs with repeated or continuous exposure to agonists. GRK-mediated phosphorylation and subsequent binding with arrestins in the activated receptor cytoplasmic cavity in competition with G proteins has been suggested as the conventional mechanism of desensitization. Along with widely accepted conventional mechanism of desensitization, studies of various GPCRs including dopamine D2-like receptors (D2R, D3R, D4R) have suggested the existence of another desensitization mechanism. In this study, loss-of-function approaches and D2-like receptor mutants that display different desensitization properties were used to elucidate the molecular mechanisms responsible for desensitization. Desensitization development entailed the signaling cascade composed of Src, PDK1, and Akt, the latter of which in turn interacted with USP33, an arrestin deubiquitinase, to promote arrestin deubiquitination. The deubiquitinated arrestin subsequently formed a complex with Gβγ and translocated to the nucleus via an importin complex, wherein it sequestered Gβγ from the receptor and Gα, thereby attenuating receptor signaling. As in D2-like receptors, both USP33 and importin β1 were involved in the desensitization of the β2 adrenoceptor. In addition to the conventional mechanism of desensitization, which occurs on the plasma membrane and in the cytosol, this study provides a new insight that another desensitization pathway in which nuclear trafficking plays a critical role is operating. It is plausible that multiple, complementary desensitization measures are in place to properly induce desensitization depending on receptor characteristics or the surrounding environment.

中文翻译：

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通过去泛素化抑制蛋白将 Gβγ 螯合到细胞核中作为 G 蛋白偶联受体的一种新型脱敏机制

G 蛋白偶联受体 (GPCR) 的脱敏是指重复或持续暴露于激动剂时发生的反应性快速减弱。GRK 介导的磷酸化和随后与活化受体细胞质腔中的抑制蛋白结合以与 G 蛋白竞争已被认为是脱敏的常规机制。除了广泛接受的常规脱敏机制外，对包括多巴胺 D2 样受体（D2R、D3R、D4R）在内的各种 GPCR 的研究表明存在另一种脱敏机制。在这项研究中，使用功能丧失方法和显示不同脱敏特性的 D2 样受体突变体来阐明导致脱敏的分子机制。脱敏发展需要由 Src、PDK1 和 Akt 组成的信号级联，后者又与抑制蛋白去泛素酶 USP33 相互作用，以促进抑制蛋白去泛素化。去泛素化抑制蛋白随后与 Gβγ 形成复合物，并通过输入蛋白复合物转运至细胞核，其中它将 Gβγ 与受体和 Gα 隔离，从而减弱受体信号传导。与 D2 样受体一样，USP33 和输入蛋白 β1 都参与了 β2 肾上腺素能受体的脱敏。除了发生在质膜和胞质溶胶中的常规脱敏机制外，这项研究提供了一个新的见解，即核运输在其中起着关键作用的另一种脱敏途径正在运作。多个是合理的，