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

backgroundDesensitization 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 (D

resultsDesensitization 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 β

conclusionsIn 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. Video Abstract.