Disease relevance of Arrb1

• Myocardial distribution and regulation of GRK and beta-arrestin isoforms in congestive heart failure in rats [1].
• Consistently, Western blot analysis of tissue extracts from the nonischemic region of the left ventricle revealed 3.0-, 2.6-, and 1.5-fold elevations of GRK2, GRK5, and beta-arrestin-1, respectively, 7 days after induction of myocardial infarction compared with the sham-operated rats (P < 0.05) [1].
• We analyzed GRK and beta-arrestin expression after cerebral hypoxia/ischemia (HI) [2].
• Fourth, the over-expression of C-terminal GRK2 peptide (which sequesters G-protein betagamma subunits) or beta-arrestin I clathrin binding domain (amino acids: 319-418) or pre-treatment of cells with pertussis toxin reduced the LPA- and NGF-dependent stimulation of p42/p44 MAPK [3].
• Expression patterns of the regulatory proteins G protein-coupled receptor kinase 2 and beta-arrestin 1 during rat postnatal brain development: effect of hypothyroidism [4].

High impact information on Arrb1

• beta-Adrenergic receptor kinase (beta ARK) and beta-arrestin function in the homologous or agonist-activated desensitization of G protein-coupled receptors [5].
• Arf6 activation releases docked beta-arrestin necessary for receptor desensitization, providing a feedback mechanism for receptor self-regulation [6].
• When endogenous beta-arrestin-1 was knocked down by transfection of beta-arrestin-1 small interfering RNA, insulin-induced IRS-1 degradation was enhanced [7].
• beta-arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR signaling [7].
• In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by beta-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation [8].

Biological context of Arrb1

• These findings demonstrate that GPCRs can utilize distinct endocytic pathways, distinguishable by dynamin and beta-arrestin, and that beta-arrestins function as adaptor proteins specifically targeting GPCRs for dynamin-dependent endocytosis via clathrin-coated vesicles [9].
• Phosphorylation of G protein-coupled receptors and the subsequent recruitment of beta-arrestin play an important role in desensitization of receptor-mediated responses, including degranulation in leukocytes [10].
• Nucleotide sequence of PCR fragments from ROS 17/2.8 cells revealed 100% identity with rat brain beta ARK1 and beta-arrestin 1 sequences [11].
• These results indicate that upregulation of beta1-ARs is associated with subcellular redistribution of GRKs and beta-arrestin-1 in the failing heart due to volume overload [12].
• To examine the mechanisms of changes in beta-adrenergic signal transduction in heart failing due to volume overload, we studied the status of beta-adrenoceptors (beta-ARs), G protein-coupled receptor kinase (GRK), and beta-arrestin in heart failure due to aortocaval shunt (AVS) [12].

Anatomical context of Arrb1

• Immunohistochemical analysis of myocardial tissue sections and Western blot analysis of isolated cells revealed localization of GRK2 and beta-arrestin-1 predominantly in endothelial cells [1].
• The expression of GRKs and beta-arrestins by gonadotropes and their inhibition of GnRH-stimulated IP3 production in COS-1 cells expressing the GnRH receptor suggest a potential regulatory role for the GRK/beta arrestin paradigm in GnRH receptor signaling [13].
• Presence of beta-arrestin-1 immunoreactivity in the cutaneous nerve fibers of rat glabrous skin [14].
• In the present study, we investigated the density and the functional activity of beta-adrenergic receptors, the enzymatic activity of beta ARK in membranes and cytosol, the mRNA levels of beta ARK-1, and the expression of beta-arrestin during stop-flow and low-flow ischemia in the isolated perfused rat heart [15].
• No changes in NK-1 receptor mRNA levels were demonstrated; however, the expression of NK-1 receptors in the plasma membrane of RAO pelvis were decreased, possibly resulting from the internalization of the receptors associated with beta-arrestin trafficking [16].

Associations of Arrb1 with chemical compounds

• Phosphorylation-independent beta-arrestin translocation and internalization of leukotriene B4 receptors [17].
• For the beta 2-adrenergic receptor (beta 2AR) system, which is coupled to adenylyl cyclase via the stimulatory guanine nucleotide-binding regulatory (G5) protein, homologous desensitization is mediated in part by a receptor-specific kinase (beta ARK) and a soluble cofactor (beta-arrestin) [11].
• Treatment of AVS animals with imidapril (1 mg.kg(-1).day(-1)) or losartan (20 mg.kg(-1).day(-1)) retarded the progression of heart failure; partially prevented changes in beta1-ARs, GRKs, and beta-arrestin-1 in the failing myocardium; and attenuated the increase in positive inotropic effect of isoproterenol [12].
• (ii) This downregulation of endogenous beta-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type beta-arrestin-1 [8].
• Presence of beta-arrestin in cellular inclusions in metamphetamine-treated PC12 cells [18].

Regulatory relationships of Arrb1

• In locus coeruleus, both acute and chronic morphine treatments resulted in significant decreases (over 50%) in beta-arrestin 1 mRNA level but failed to induce any change in the level of beta-arrestin 2 gene expression [19].

Other interactions of Arrb1

• Thus loop 3 and the COOH tail specify colocalization of the NK1R with beta-arrestin 1 and determine the rate of resensitization [20].
• Hypoxia/ischemia modulates G protein-coupled receptor kinase 2 and beta-arrestin-1 levels in the neonatal rat brain [2].
• Both GRK2 and beta-arrestin I are involved in clathrin-mediated endocytic signaling to p42/p44 MAPK [21].
• Additionally, confocal microscopy showed that activated GnRH-Rs failed to induce time-dependent redistribution of either beta-arrestin-1- or beta-arrestin-2-green fluorescent protein conjugate to the plasma membrane [22].
• These alterations are selective, as beta-adrenergic receptors or other G protein-coupled receptor regulatory proteins, such as G protein-coupled receptor kinase 5 or beta-arrestin-1, display a different pattern of expression changes in the hypothyroid animals [23].

Analytical, diagnostic and therapeutic context of Arrb1

• Dual-label immunofluorescence confocal microscopic studies of rat cortex indicated that many cortical pyramidal neurons coexpressed arrestins (beta-arrestin or arrestin-3) and 5-HT2A receptors, particularly in intracellular vesicles [24].
• The involvement of beta-arrestin in UPP was further supported by electron microscopy and by confocal microscopy, which documented the presence of beta-arrestin in these Lewy body-like inclusions [18].

References