title: β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia.
abstract: Microglial activation worsens neuronal loss and contributes to progressive neurological diseases like Parkinson's disease (PD). This inflammatory progression is countered by dynorphin (Dyn), the endogenous ligand of the kappa-opioid receptor (KOR). We show that microglial β-arrestin mediates the ability of Dyn/KOR to limit endotoxin-elicited production of pro-inflammatory effectors and cytokines, subsequently protecting neurons from inflammation-induced neurotoxicity. Agonist-activated KOR enhances the interaction of β-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), disrupting TAK1-TAB1 mediated pro-inflammatory gene expression. We reveal a new physiological role for β-arrestin in neuroprotection via receptor internalization-triggered blockade of signal effectors of microglial inflammatory neurotoxicity. This result offers novel drug targets in the convergent KOR/β-arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: F H
authors.initials: FH
authors.lastname: Burton
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Loh
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: L-N
authors.initials: LN
authors.lastname: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004399:Dynorphins / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018847:Opioid Peptides / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D000071557:beta-Arrestins; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019390:Arrestins; D016207:Cytokines; D004399:Dynorphins; D020930:MAP Kinase Kinase Kinases; D018847:Opioid Peptides; D017473:Receptors, Opioid, kappa; D000071557:beta-Arrestins; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse