title: δ-Opioid receptors up-regulate excitatory amino acid transporters in mouse astrocytes.
abstract: OBJECTIVE
  Astrocytic excitatory amino acid transporters (EAATs) regulate extracellular glutamate concentrations and play a role in preventing neuroexcitotoxicity. As the δ-opioid receptor (DOP receptor) is neuroprotective against excitotoxic injury, we determined whether DOP receptor activation up-regulates EAAT expression and function.
  
  
  METHODS
  We measured mRNA and protein expression of EAAT1, EAAT2 and EAAT3 in cultured mouse astrocytes exposed to a specific DOP receptor agonist (UFP-512) with or without a DOP receptor antagonist, DOP receptor siRNA or inhibitors of PKC, PKA, PI3K, p38, MAPK, MEK and ERK, and evaluated the function of EAATs by measuring glutamate uptake.
  
  
  RESULTS
  Astrocytic DOP receptor mRNA and protein were suppressed by DOP receptor siRNA knockdown. DOP receptor activation increased mRNA and protein expression of EAAT1 and EAAT2, but not EAAT3, thereby enhancing glutamate uptake of astrocytes. DOP receptor-induced EAAT1 and EAAT2 expression was largely reversed by DOP receptor antagonist naltrindole or by DOP receptor siRNA knockdown, and suppressed by inhibitors of MEK, ERK and p38. DOP receptor-accelerated glutamate uptake was inhibited by EAAT blockers, DOP receptor siRNA knockdown or inhibitors of MEK, ERK or p38. In contrast, inhibitors of PKA, PKC or PI3K had no significant effect on DOP receptor-induced EAAT expression.
  
  
  CONCLUSIONS
  DOP receptor activation up-regulates astrocytic EAATs via MEK-ERK-p38 signalling, suggesting a critical role for DOP receptors in the regulation of astrocytic EAATs and protection against neuroexcitotoxicity. As decreased EAAT expression contributes to pathophysiology in many neurological diseases, including amyotrophic lateral sclerosis, our findings present a new platform for potential treatments of these diseases.
authors: Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX, USA; Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China.
authors: Jianfeng
authors: J
authors: Liang
authors: Dongman
authors: D
authors: Chao
authors: Harleen K
authors: HK
authors: Sandhu
authors: Yanbing
authors: Y
authors: Yu
authors: Li
authors: L
authors: Zhang
authors: Gianfranco
authors: G
authors: Balboni
authors: Dong H
authors: DH
authors: Kim
authors: Ying
authors: Y
authors: Xia
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C526539:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide; D001562:Benzimidazoles; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D009292:Narcotic Antagonists; D009842:Oligopeptides; D034741:RNA, Small Interfering; D017465:Receptors, Opioid, delta; C493399:Slc1a1 protein, mouse; C493396:Slc1a2 protein, mouse; C493393:Slc1a3 protein, mouse; D009271:Naltrexone; C055382:naltrindole