Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of signaling receptors and control a vast array of physiological responses. Modulating the signaling responses of GPCRs therapeutically is important for the treatment of various diseases, and discovering new aspects of GPCR signal regulation is critical for future drug development. Post-translational modifications are integral to the regulation of GPCR function. In addition to phosphorylation, many GPCRs are reversibly modified with ubiquitin. Ubiquitin is covalently attached to lysine residues within the cytoplasmic domains of GPCRs by ubiquitin ligases and removed by ubiquitin-specific proteases. In many cases, ubiquitin functions as a sorting signal that facilitates trafficking of mammalian GPCRs from endosomes to lysosomes for degradation, but not all GPCRs use this pathway. Moreover, there are distinct types of ubiquitin conjugations that are known to serve diverse functions in controlling a wide range of cellular processes, suggesting broad roles for GPCR ubiquitination. In this review, we highlight recent studies that illustrate various roles for ubiquitin in regulation of GPCR function. Ubiquitination is known to target many GPCRs for lysosomal degradation, and current studies now indicate that basal ubiquitination, deubiquitination, and transubiquitination of certain GPCRs are important for controlling cell surface expression and cellular responsiveness. In addition, novel functions for ubiquitin in regulation of GPCR dimers and in mediating differential GPCR regulation induced by biased agonists have been reported. We will discuss the implications of these new discoveries for ubiquitin regulation of GPCR function in the context of drug development.