Current TopicsNovel roles for arrestins in the post-endocytic trafficking of G protein-coupled receptors
Introduction
G protein-coupled receptors (GPCRs) represent the largest and perhaps most evolutionarily widespread family of transmembrane signaling molecules. The superfamily consists of at least 600 members in the human genome and responds to a diverse array of signals including light, odorants, nucleotides, small molecule amines, ions, lipids, steroids, amino acids and peptides ranging from large glycoproteins to oligopeptides (Gether, 2000). GPCRs are involved in a variety of systems, from sensory (vision, smell, taste) to metabolic and physiologic maintenance (cardiac, hepatic and immune regulation, hormone release) to neurologic function (cognition, pain, analgesia). From this, it is clear that there must exist a multitude of mechanisms by which the signals from GPCRs are initiated, propagated, attenuated, regulated, terminated and reinitiated. All GPCR-mediated signaling begins with the activation of the receptor through the binding of agonist, resulting in a conformational change within the intracellular domains of the receptor, which can then be recognized by intracellular proteins (Hunyady et al., 2003). Although more and more activated GPCRs are being shown to be able to interact directly with cytoplasmic effector proteins (Brady and Limbird, 2002), the most common signal transducing proteins are the heterotrimeric G proteins (Hamm, 1998). The conventional effectors of G proteins are phospholipases, phosphodiesterases, adenylyl cyclases, phosphatidyl inositol kinases and ion channels to name a few. In addition, activated GPCRs are the target of G protein-coupled receptor kinases, which phosphorylate GPCRs on serine and threonine residues of intracellular domains, usually within the carboxy terminus Kohout and Lefkowitz, 2003, Penn et al., 2000. This phosphorylation leads to the rapid recruitment and binding of cytosolic arrestins (known as arrestin-2 or β-arrestin-1 and arrestin-3 or β-arrestin-2). It is now appreciated that arrestin binding initiates entirely new sequences of events from receptor desensitization and internalization to scaffolding of kinases to controlling intracellular trafficking of GPCRs following endocytosis Marchese et al., 2003, Seachrist and Ferguson, 2003, Shenoy and Lefkowitz, 2003a, Shenoy and Lefkowitz, 2003b, Zastrow, 2003. This review will summarize how arrestins are centrally involved in GPCR function through the regulation of post-endocytic trafficking.
Section snippets
Modes of GPCR endocytosis
Following activation by agonist, virtually all GPCRs undergo ligand-induced endocytosis. This process was originally thought to represent a mechanism primarily to remove “spent” (i.e. desensitized) receptors from the cell surface. But it is now recognized that this process in fact serves a number of purposes. These include the regulation of cell surface protein expression levels to modulate cellular responsiveness to ligands (Krupnick and Benovic, 1998), localization of intracellular signaling
GPCR and arrestin trafficking during endocytosis
It is perhaps surprising that despite the existence of a great diversity of internalization mechanisms, virtually all GPCRs examined bind arrestins following activation. This may reflect a common function in desensitization but raises the question as to how a GPCR that internalizes in a phosphorylation-dependent yet arrestin-independent manner manages to bind arrestin through the same phosphorylation sites that are apparently used to mediate internalization. This apparent conflict might be
Post-endocytic GPCR trafficking and recycling
Once internalized, a GPCR can experience one of two fates. Either the receptor is degraded or it is recycled in a functional state back to the plasma membrane. Clearly, the sequences of the intracellular domains of a GPCR, and by inference the pattern of phosphorylation sites and thus the binding properties of arrestins, exert great effects on the intracellular trafficking of an internalized receptor. Recently, arrestin ubiquitination and dequbiquitination have been shown to correlate with
Conclusion
In conclusion, the regulation of GPCR function is a complex process that is tightly controlled both spatially and temporally. Arrestins represent the primary binding partner of activated, phosphorylated GPCRs and as such are positioned to play a central role in their regulation. Originally thought only to be involved in GPCR desensitization, arrestins are now known to be involved in receptor endocytosis, adapter and kinase scaffolding, intracellular trafficking and most recently to be required
Acknowledgements
The author is supported by NIH grants AI36357, AI43932 and GM68901. Institutional support at the University of New Mexico Health Sciences Center is provided from NCRR 1 S10 RR14668, NSF MCB9982161, NCRR P20 RR11830, NCI R24 CA88339, and the University of New Mexico Cancer Research and Treatment Center. Due to space limitations, it was not possible to cite all the primary literature that has contributed to our knowledge of the topics addressed in this review.
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