Elsevier

Life Sciences

Volume 75, Issue 8, 9 July 2004, Pages 893-899
Life Sciences

Current Topics
Novel roles for arrestins in the post-endocytic trafficking of G protein-coupled receptors

https://doi.org/10.1016/j.lfs.2004.04.003Get rights and content

Abstract

G protein-coupled receptors (GPCRs) represent the largest family of transmembrane signaling molecules in the human genome. As such, they interact with numerous intracellular molecules, which can act either to propagate or curtail signaling from the receptor. Their primary mode of cellular activation occurs through heterotrimeric G proteins, which in turn can activate a wide spectrum of effector molecules, including phosphodiesterases, phospholipases, adenylyl cyclases and ion channels. Active GPCRs are also the target of G protein-coupled receptor kinases, which phosphorylate the receptors culminating in the binding of the protein arrestin. This results in rapid desensitization through inhibition of G protein binding, as well as novel mechanisms of cellular activation that involve the scaffolding of cellular kinases to GPCR-arrestin complexes. Arrestins can also serve to mediate the internalization of certain GPCRs, a process which plays an important role in regulating cellular activity both by mediating long-term desensitization through down regulation (degradation) of receptors and by recycling desensitized receptors back to the cell surface to initiate additional rounds of signaling. The mechanisms that regulate the subsequent intracellular trafficking of GPCRs following internalization are largely unknown. Recently however, it has become clear that the pattern of receptor phosphorylation and subsequent binding of arrestin play a critical role in the intracellular trafficking of internalized receptors, thereby dictating the ultimate fate of the receptor. In addition, arrestins have now been shown to be required for the recycling of GPCRs that are capable of internalizing through arrestin-independent mechanisms. This review will summarize recent advances in our understanding of the roles of arrestins in post-endocytic GPCR trafficking.

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.

References (41)

  • K McConalogue et al.

    Substance P-induced trafficking of beta-arrestins. The role of beta-arrestins in endocytosis of the neurokinin-1 receptor

    Journal of Biological Chemistry

    (1999)
  • W.E Miller et al.

    beta-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor endocytosis

    Journal of Biological Chemistry

    (2000)
  • R.H Oakley et al.

    Association of beta-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization

    Journal of Biological Chemistry

    (1999)
  • R.H Oakley et al.

    Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis

    Journal of Biological Chemistry

    (2001)
  • R.H Oakley et al.

    Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors

    Journal of Biological Chemistry

    (2000)
  • M.M Paing et al.

    beta -Arrestins regulate protease-activated receptor-1 desensitization but not internalization or down-regulation

    Journal of Biological Chemistry

    (2002)
  • R Pals-Rylaarsdam et al.

    Internalization of the m2 muscarinic acetylcholine receptor. Arrestin- independent and -dependent pathways

    Journal of Biological Chemistry

    (1997)
  • L Pan et al.

    The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor

    Journal of Biological Chemistry

    (2003)
  • R.B Penn et al.

    Regulation of G protein-coupled receptor kinases

    Trends in Cardiovascular Medicine

    (2000)
  • R.M Potter et al.

    Arrestin variants display differential binding characteristics for the phosphorylated N-formyl peptide receptor carboxyl terminus

    Journal of Biological Chemistry

    (2002)
  • Cited by (45)

    • Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors

      2017, Cellular Signalling
      Citation Excerpt :

      The putative usefulness of an enhanced arrestin molecule in compensational gene therapy has already been proven with an enhanced form of arrestin-1, which prolonged photoreceptor survival and improved rod function in rhodopsin kinase-deficient mice [11]. Non-visual arrestins can be pre-activated by homologous mutations [17,18,80,81]. Enhanced versions of non-visual arrestins can quench hyperactive GPCRs in all cell types where excessive receptor signaling underlies disease state [1,2].

    • Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines

      2013, Journal of Biological Chemistry
      Citation Excerpt :

      Likewise, as suggested (52), PSD-95 can scaffold together other proteins to form larger protein complexes that are possibly resistant to internalization. Lastly, PSD-95 association to the cytosolic portions of GPR30 (4, 76, 77) might sterically block the access of other cytosolic proteins that are important for receptor internalization, such as β-arrestins (78). GPR30, however, has been recently shown to undergo clathrin-mediated and potentially β-arrestin-independent constitutive endocytosis instead (79).

    • Dephosphorylation of endogenous GABA<inf>B</inf> receptor R2 subunit and AMPK α subunits which were measured by in vitro method using transfer membrane

      2013, Neurochemistry International
      Citation Excerpt :

      These facts indicate that GABAB receptor regulation does not fit the classical model for monomeric GPCRs. According to this classical model, receptor phosphorylation on serine or threonine residues by kinases (G protein-coupled receptor kinases, PKA, PKC and others) induces β-arrestin binding, which uncouples the receptor from G proteins and promotes its internalization, followed by either degradation or receptor recycling after dephosphorylation (Luttrell and Lefkowitz, 2002; Prossnitz, 2004). Thus, phosphorylation of monomeric GPCRs promotes their desensitization, whereas phosphorylation of the GABAB receptor at S783 or S892 appears to have an opposite effect.

    • Nongenomic actions of aldosterone and progesterone revisited

      2012, Steroids
      Citation Excerpt :

      GPR30 represents a heptahelical transmembrane protein acting as a G-protein coupled receptor [21]. The binding of agonists initiates activation of heterotrimeric guanine nucleotide-binding proteins (G-Proteins), downstream regulators such as arrestins [22] and actors, for example adenylyl cyclase and phospholipase C-β [23]. GPR30 was originally postulated to mediate rapid actions of estrogen [20], but discrepancies on GPR30 features exist between different working groups.

    View all citing articles on Scopus
    View full text