Disease relevance of Arrb2

• Endotoxin-treated beta-arrestin 2-deficient mice had higher expression of proinflammatory cytokines and were more susceptible to endotoxic shock [1].
• Studies in mice have shown that beta-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation, and respiratory depression [2].

High impact information on Arrb2

• Importantly, canonical cAMP-mediated dopamine-receptor signaling is not inhibited in the absence of beta-arrestin 2 [3].
• Furthermore, this function of beta-arrestin 2 is important for the expression of dopamine-associated behaviors, thus implicating beta-arrestin 2 as a positive mediator of dopaminergic synaptic transmission and a potential pharmacological target for dopamine-related psychiatric disorders [3].
• However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug [4].
• These results provide evidence in vivo for the physiological importance of beta-arrestin 2 in regulating the function of a specific GPCR, the muOR [5].
• It has been reported recently that T cells lacking beta-arrestin-2, a G protein-coupled receptor regulatory protein, demonstrate impaired migration in vitro [6].

Biological context of Arrb2

• Histomorphometry showed that PTH-stimulated periosteal bone formation was 2-fold higher in beta-arr2(-/-) compared with WT [7].
• The Cys328/329-Ser mutant, which is constitutively active in the absence of ligand, exhibited enhanced receptor phosphorylation under both basal and agonist-stimulated conditions and was more effectively desensitized and internalized via a beta-arrestin-2 mediated pathway compared with the wild-type 5-HT4a [8].
• Differential regulation of beta-arrestin 1 and beta-arrestin 2 gene expression in rat brain by morphine [9].

Anatomical context of Arrb2

• beta-Arrestin 2 expression determines the transcriptional response to lysophosphatidic acid stimulation in murine embryo fibroblasts [10].
• Here we show that allergen-sensitized mice having a targeted deletion of the beta-arrestin-2 gene do not accumulate T lymphocytes in their airways, nor do they demonstrate other physiological and inflammatory features characteristic of asthma [6].
• However, after chronic morphine treatment, beta-arrestin 2 mRNA level decreased by 40% in periaqueductal gray and increased by 25% in cerebral cortex, in strong contrast to the unchanged beta-arrestin 1 mRNA level in these two brain regions [9].
• The acute morphine administration had no significant effect on beta-arrestin 1 or beta-arrestin 2 mRNA level in periaqueductal gray and cerebral cortex [9].
• Furthermore, spontaneous or naloxone-precipitated withdrawal of morphine that did not affect the level of beta-arrestin 1 mRNA resulted in an aberrant increase (100% over control) in beta-arrestin 2 mRNA level in hippocampus [9].

Associations of Arrb2 with chemical compounds

• At 30 min, endogenous beta-arrestins reduced TRH-stimulated inositol phosphate production by 48% (beta-arrestin-1), 71% (beta-arrestin-2), and 84% (beta-arrestins-1 and -2) [11].
• The present result suggests that beta-arrestin-2 may tonically down-regulate a selected population of mu-opioid receptors activated by endomorphin-1 or DAMGO in the mouse spinal cord [12].
• Intrathecal (i.t.) pretreatment with beta-arrestin-2 antibody potentiated the antinociception induced by i.t.-administered mu-opioid receptor agonists [D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) and endomorphin-1, but not endomorphin-2, the delta-opioid receptor agonist [D-Ala(2)]deltorphin II or the kappa-opioid receptor agonist U50,488H [12].
• Receptor functionality was assessed by Ang II-stimulated beta-arrestin 2 translocation and showed an Ang II-mediated response in wild type but not (AT(1A) [-/ -], AT(1B) [-/-]) cells [13].

Other interactions of Arrb2

• Comparison of the ability of the two beta-arrestins to sequester the beta(2)-AR revealed beta-arrestin 2 to be 100-fold more potent than beta-arrestin 1 [14].
• Functional deletion of the beta-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that muOR desensitization was impaired [5].
• We have previously shown that adaptor protein beta-arrestin-2 (betaarr2) plays a crucial role in transducing signals mediated through CXCR2 [15].

Analytical, diagnostic and therapeutic context of Arrb2

• Enhanced morphine analgesia in mice lacking beta-arrestin 2 [5].
• In the current study, we investigated the potential regulatory effects of morphine administration on beta-arrestin 1 and beta-arrestin 2 mRNA levels in different brain regions in rat using in situ hybridization method [9].

References