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Pharmacological Reviews Sep 2023The two -arrestins, -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a... (Review)
Review
The two -arrestins, -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiologic functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both -arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how -arrestins bind to activated GPCRs and downstream effector proteins. Studies with -arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by -arrestin-1 and/or -2. Following a short summary of recent structural studies, this review primarily focuses on -arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of -arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review also highlights potential therapeutic implications of these studies and discusses strategies that could prove useful for targeting specific -arrestin-regulated signaling pathways for therapeutic purposes. SIGNIFICANCE STATEMENT: The two β-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. The outcome of studies with β-arrestin mutant mice and cultured cells, complemented by novel insights into β-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific β-arrestin functions.
Topics: Mice; Animals; beta-Arrestins; Arrestins; Signal Transduction; Receptors, G-Protein-Coupled; beta-Arrestin 1
PubMed: 37028945
DOI: 10.1124/pharmrev.121.000302 -
Cell Nov 2022Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of...
Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics.
Topics: Humans; Analgesics, Opioid; Arrestin; Fentanyl; GTP-Binding Proteins; Morphine; Receptors, Opioid, mu
PubMed: 36368306
DOI: 10.1016/j.cell.2022.09.041 -
Cell Nov 2022Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with...
Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with β-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for β-arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state of the complex. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for β-arrestin release upon translocation of the GPCR to endosomes, allowing for its rapid recycling.
Topics: beta-Arrestins; Phosphatidylinositols; Arrestins; beta-Arrestin 1; Receptors, G-Protein-Coupled
PubMed: 36368322
DOI: 10.1016/j.cell.2022.10.018 -
Biomolecules Feb 2021Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at... (Review)
Review
Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at least three functions: precluding further receptor coupling to G proteins, facilitating receptor internalization, and initiating distinct arrestin-mediated signaling. The molecular mechanism of arrestin-GPCR interactions has been extensively studied and discussed from the "arrestin perspective", focusing on the roles of arrestin elements in receptor binding. Here, we discuss this phenomenon from the "receptor perspective", focusing on the receptor elements involved in arrestin binding and emphasizing existing gaps in our knowledge that need to be filled. It is vitally important to understand the role of receptor elements in arrestin activation and how the interaction of each of these elements with arrestin contributes to the latter's transition to the high-affinity binding state. A more precise knowledge of the molecular mechanisms of arrestin activation is needed to enable the construction of arrestin mutants with desired functional characteristics.
Topics: Animals; Arrestin; Arrestins; Binding Sites; Cattle; Crystallography, X-Ray; Fishes; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Models, Molecular; Mutation; Phosphorylation; Protein Binding; Protein Conformation; Protein Domains; Protein Isoforms; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 33557162
DOI: 10.3390/biom11020218 -
Current Opinion in Structural Biology Aug 2017The large and multifunctional family of G protein-coupled receptors (GPCRs) are regulated by a small family of structurally conserved arrestin proteins. In order to bind... (Review)
Review
The large and multifunctional family of G protein-coupled receptors (GPCRs) are regulated by a small family of structurally conserved arrestin proteins. In order to bind an active GPCR, arrestin must first be activated by interaction with the phosphorylated receptor C-terminus. Recent years have witnessed major developments in high-resolution crystal structures of pre-active arrestins and arrestin or arrestin-derived peptides in complex with an active GPCR. Although each structure individually offers only a limited snapshot, taken together and interpreted in light of recent complementary functional data, they offer valuable insight into how arrestin is activated by and couples to a phosphorylated active GPCR.
Topics: Animals; Arrestin; Humans; Protein Domains; Rotation
PubMed: 28600951
DOI: 10.1016/j.sbi.2017.05.001 -
International Journal of Molecular... Jun 2022Three out of four subtypes of arrestin proteins expressed in mammals self-associate, each forming oligomers of a distinct kind. Monomers and oligomers have different... (Review)
Review
Three out of four subtypes of arrestin proteins expressed in mammals self-associate, each forming oligomers of a distinct kind. Monomers and oligomers have different subcellular localization and distinct biological functions. Here we summarize existing evidence regarding arrestin oligomerization and discuss specific functions of monomeric and oligomeric forms, although too few of the latter are known. The data on arrestins highlight biological importance of oligomerization of signaling proteins. Distinct modes of oligomerization might be an important contributing factor to the functional differences among highly homologous members of the arrestin protein family.
Topics: Animals; Arrestin; Arrestins; Mammals; beta-Arrestins
PubMed: 35806256
DOI: 10.3390/ijms23137253 -
Cellular Signalling Jun 2022G-protein coupled receptor (GPCR) kinases (GRKs) and β-arrestins play key roles in GPCR and non-GPCR cellular responses. In fact, GRKs and arrestins are involved in a... (Review)
Review
G-protein coupled receptor (GPCR) kinases (GRKs) and β-arrestins play key roles in GPCR and non-GPCR cellular responses. In fact, GRKs and arrestins are involved in a plethora of pathways vital for physiological maintenance of inter- and intracellular communication. Here we review decades of research literature spanning from the discovery, identification of key structural elements, and findings supporting the diverse roles of these proteins in GPCR-mediated pathways. We then describe how GRK2 and β-arrestins partake in non-GPCR signaling and briefly summarize their involvement in various pathologies. We conclude by presenting gaps in knowledge and our prospective on the promising pharmacological potential in targeting these proteins and/or downstream signaling. Future research is warranted and paramount for untangling these novel and promising roles for GRK2 and arrestins in metabolism and disease progression.
Topics: Arrestins; G-Protein-Coupled Receptor Kinases; Phosphorylation; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestin 1; beta-Arrestin 2; beta-Arrestins
PubMed: 35430346
DOI: 10.1016/j.cellsig.2022.110333 -
Neuropharmacology Jul 2017Arrestins play a prominent role in shutting down signaling via G protein-coupled receptors. In recent years, a signaling role for arrestins independent of their function...
Arrestins play a prominent role in shutting down signaling via G protein-coupled receptors. In recent years, a signaling role for arrestins independent of their function in receptor desensitization has been discovered. Two ubiquitously expressed arrestin isoforms, arrestin-2 and arrestin-3, perform similarly in the desensitization process and share many signaling functions, enabling them to substitute for one another. However, signaling roles specific to each isoform have also been described. Mice lacking arrestin-3 (ARR3KO) were reported to show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). It has been suggested that mice with deletion of arrestin-2 display a similar phenotype. Here we demonstrate that the AMPH-induced locomotion of male ARR3KO mice is reduced over the 7-day treatment period and during AMPH challenge after a 7-day withdrawal. The data are consistent with impaired locomotor sensitization to AMPH and suggest a role for arrestin-3-mediated signaling in the sensitization process. In contrast, male ARR2KO mice showed enhanced early responsiveness to AMPH and the lack of further sensitization, suggesting a role for impaired receptor desensitization. The comparison of mice possessing one allele of arrestin-3 and no arrestin-2 with ARR2KO littermates revealed reduced activity of the former line, consistent with a contribution of arrestin-3-mediated signaling to AMPH responses. Surprisingly, ARR3KO mice with one arrestin-2 allele showed significantly reduced locomotor responses to AMPH combined with lower novelty-induced locomotion, as compared to the ARR3KO line. These data suggest that one allele of arrestin-2 is unable to support normal locomotor behavior due to signaling and/or developmental defects.
Topics: Amphetamine; Analysis of Variance; Animals; Arrestins; Central Nervous System Stimulants; Locomotion; Mice; Mice, Inbred C57BL; Mice, Knockout; Time Factors; beta-Arrestin 1
PubMed: 28419873
DOI: 10.1016/j.neuropharm.2017.04.021 -
Protein & Cell Dec 2018Arrestins are soluble relatively small 44-46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are... (Review)
Review
Arrestins are soluble relatively small 44-46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations: free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures. However, protein-protein interactions often involve highly flexible elements that can assume many distinct conformations upon binding to different partners. Existing evidence suggests that arrestins are no exception to this rule: their flexibility is necessary for functional versatility. The data on arrestins and many other multi-functional proteins indicate that in many cases, "order" might be artificially imposed by highly non-physiological crystallization conditions and/or crystal packing forces. In contrast, conformational flexibility (and its extreme case, intrinsic disorder) is a more natural state of proteins, representing true biological order that underlies their physiologically relevant functions.
Topics: Animals; Arrestins; Humans; Protein Conformation
PubMed: 29453740
DOI: 10.1007/s13238-017-0501-8 -
International Journal of Molecular... Apr 2022α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary... (Review)
Review
α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly unexplored. The predominant function of α-arrestins is the selective identification of membrane proteins for ubiquitination and degradation, which is an important element in maintaining membrane protein homeostasis as well as global cellular metabolisms. Among members of the arrestin clan, only α-arrestins possess PY motifs that allow canonical binding to WW domains of Rsp5/NEDD4 ubiquitin ligases and the subsequent ubiquitination of membrane proteins leading to their vacuolar/lysosomal degradation. The molecular mechanisms of the selective substrate's targeting, function, and regulation of α-arrestins in response to different stimuli remain incompletely understood. Several functions of α-arrestins in animal models have been recently characterized, including redox homeostasis regulation, innate immune response regulation, and tumor suppression. However, the molecular mechanisms of α-arrestin regulation and substrate interactions are mainly based on observations from the yeast model. Nonetheless, α-arrestins have been implicated in health disorders such as diabetes, cardiovascular diseases, neurodegenerative disorders, and tumor progression, placing them in the group of potential therapeutic targets.
Topics: Animals; Arrestin; Arrestins; Endocytosis; Humans; Neoplasms; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquitination
PubMed: 35563378
DOI: 10.3390/ijms23094988