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?-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 ?-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 ?-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 ?-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/?-arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD.

SUBMITTER: Feng X

PROVIDER: S-EPMC3921587 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia.

Feng X X Wu C-Y CY Burton F H FH Loh H H HH Wei L-N LN

Cell death and differentiation 20131025 3

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 enhan ...[more]

PMID: 24162663

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?-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia.

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β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia.

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