Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein-coupled receptors

Background 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. Results 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 G beta gamma and translocated to the nucleus via an importin complex, wherein it sequestered G beta gamma from the receptor and G alpha, thereby attenuating receptor signaling. As in D2-like receptors, both USP33 and importin beta 1 were involved in the desensitization of the beta(2) adrenoceptor. Conclusions 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.

Automated summary

In addition to the conventional mechanism of desensitization, this study reveals that there is another desensitization pathway involving nuclear trafficking. This pathway is mediated by Src, PDK1, Akt, and USP33, and it attenuates receptor signaling.