A novel molecular mechanism responsible for phosphorylation-independent desensitization of G protein-coupled receptors exemplified by the dopamine D₃ receptor.

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.

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