Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [R01-GM090689]; National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL073328]; and University of California Tobacco-Related Disease Research Program [Postdoctoral Fellowship 19FT-0157].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- GPCR
- G protein-coupled receptor
- USP
- ubiquitin-specific protease
- UBDs
- ubiquitin-binding domains
- ESCRT
- endosomal sorting complex required for transport
- MVB
- multivesicular bodies
- ILV
- intraluminal vesicles
- PAR
- protease-activated receptor
- DOR
- δ-opioid receptor
- HRS
- hepatocyte growth factor-regulated tyrosine kinase substrate
- ER
- endoplasmic reticulum
- AT1R
- angiotensin-II type 1 receptor
- D5R
- dopamine D5 receptor
- S1P
- sphingosine-1-phosphate
- MOR
- μ-opioid receptor
- PTH
- parathyroid hormone
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin.
- Received April 18, 2012.
- Accepted June 14, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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