title: Beta-arrestin1 and 2 differently modulate metabotropic glutamate receptor 7 signaling in rat developmental sevoflurane-induced neuronal apoptosis.
abstract: Beta-arrestins (β-arrs) are initially known as negative regulators of G protein-coupled receptors (GPCRs). Recently, there is increasing evidence suggesting that β-arrs also serve as scaffolds and adapters that mediate distinct intracellular signal transduction initiated by GPCR activation. In the previous study, we have shown that metabotropic glutamate receptor 7 (mGluR7) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling may be involved in the developmental sevoflurane neurotoxicity. In the present study, we showed that activation of mGluR7 with a group III mGluRs orthosteric agonist LAP4 or an atypical mGluR7 allosteric agonist N,N'-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082) significantly attenuated sevoflurane-induced neuronal apoptosis. Interestingly, this neuroprotective role of LAP4 could be partially reduced by β-arr1 small interfering RNA (siRNA) or β-arr2 siRNA transfection. In contrast, β-arr2 siRNA transfection alone abolished the effects of AMN082 on sevoflurane neurotoxicity. In addition, administration of LAP4 or AMN082 significantly enhanced Phospho-ERK1/2 in sevoflurane neurotoxicity, which could be abrogated by β-arr2 siRNA transfection, but not by β-arr1 siRNA transfection. Increased β-arr2-dependent Phospho-ERK1/2 signaling alleviated sevoflurane neurotoxicity by inhibiting bad phosphorylation. We also found that the neuroprotective role of AMN082 was completely reversed by ERK1/2 inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126). Alternatively, treatment with U0126 partially suppressed the neuroprotective of LAP4, suggesting that other mechanisms may be implicated in this process. Further investigation indicated that, in the scenario of sevoflurane neurotoxicity, application of LAP4 (but not AMN082) increased the interaction of β-arrs with transcriptional factors CREB binding protein (CBP) and p300. LAP4 also enhanced the β-arr1-dependent H3 and H4 acetylation in sevoflurane neurotoxicity. For the behavior study, treatment with LAP4 or AMN082 significantly improved the emotional and spatial learning and memory disorders induced by postnatal sevoflurane exposure. These results suggested that β-arr1 and 2 may differently modulate mGluR7 signaling in developmental sevoflurane neurotoxicity. This study also reveals a β-arr-biased agonism at GPCRs (e.g. mGluR7).
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China. Electronic address: Neuro-anesth@hotmail.com.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
authors.forename: H-H
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: F
authors.initials: F
authors.lastname: Cai
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: W-C
authors.initials: WC
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, Hangzhou, China. Electronic address: hushuangfei77@sina.com.
authors.forename: S-F
authors.initials: SF
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D050882:CREB-Binding Protein; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008738:Methyl Ethers / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605256:Arrb1 protein, rat; C000605257:Arrb2 protein, rat; D019390:Arrestins; D001559:Benzhydryl Compounds; D018683:Excitatory Amino Acid Agents; D008738:Methyl Ethers; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C102719:metabotropic glutamate receptor 7; D000077149:Sevoflurane; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat
keywords: ERK1/2; apoptosis; developing brain; mGluR7; sevoflurane; β-arrestins