The role and mechanism of β-arrestin2 in signal transduction

Ma, Teng; Zhou, Yong; Zhang, Chenyu; Gao, Ziang; Duan, Jia‐Xi

doi:10.1016/j.lfs.2021.119364

Cited by 16 publications

(19 citation statements)

References 111 publications

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“…As a scaffold protein, β-arrestin2 binds to multiple proteins to transduce the cellular signals [ 47 ]. It was also shown in our previous study that β-arrestin2 interacts with inflammasome component to suppress its activation [ 48 ].…”

Section: Resultsmentioning

confidence: 99%

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Yang

Song

Yao

et al. 2022

J Neuroinflammation

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Background Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. Methods We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. Results Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. Conclusions Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

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Section: Resultsmentioning

confidence: 99%

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Yang

Song

Yao

et al. 2022

J Neuroinflammation

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“…It was recently shown that after short-term stimulation GPR183 is trafficked to late endosomes and the Golgi apparatus before being recycled back to the membrane (Velasco-Estevez et al, 2021). βarrestin 2 is a scaffold protein that regulates the internalization and desensitization of GPCRs but can also mediate G-protein independent signal transduction after GPCR internalization, including MAPK and NF-κB pathways (Ma et al, 2021). GPCR signaling through βarrestins is important in biased signaling and differential effects of agonists (Wootten et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Activation of GPR183 by 7α,25-Dihydroxycholesterol Induces Behavioral Hypersensitivity through Mitogen-Activated Protein Kinase and Nuclear Factor-κB

Braden

Campolo

Liu

et al. 2022

J Pharmacol Exp Ther

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“…Then, the GPCRs are either recycled back to the plasma membrane in an active, ligand-free state, or they are sorted within the endocytic pathway and packaged into intraluminal vesicles, forming multivesicular bodies that fuse with lysosomes, and this leads to complete degradation of the receptors [ 27 , 28 ]. At the turn of 1990–2000, the participation of β-arrestins in GPCR-mediated regulation of the mitogen-activated protein kinases (MAPKs) and several other effector proteins and transcription factors were demonstrated [ 21 , 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. This has changed the paradigm of the exclusive role of the heterotrimeric G proteins as signal transducers in GPCR-signaling.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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The role and mechanism of β-arrestin2 in signal transduction

Cited by 16 publications

References 111 publications

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Activation of GPR183 by 7α,25-Dihydroxycholesterol Induces Behavioral Hypersensitivity through Mitogen-Activated Protein Kinase and Nuclear Factor-κB

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

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