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Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes.

ABSTRACT: Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.

SUBMITTER: Meyer LC

PROVIDER: S-EPMC5766282 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes.

Meyer Logan C LC Paisley Caitlin E CE Mohamed Esraa E Bigbee John W JW Kordula Tomasz T Richard Hope H Lutfy Kabirullah K Sato-Bigbee Carmen C

Glia 20170914 12

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early sta ...[more]

PMID: 28906039

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Project description:Changes in glutamatergic neurotransmission via decreased glutamate transporter (GLT) activity or expression contributes to multiple neurological disorders. Chemokines and their receptors are involved in neurological diseases but the role of chemokines in the expression of glutamate transporters is unclear.Primary astrocytes were prepared from neonatal (<24 hours old) SJL/J mouse brains and incubated with 5 ?g/ml lipopolysaccharide (LPS) or 50 ng/ml tumor necrosis factor ? (TNF-?) for 24 hours. Soluble macrophage inflammatory protein-2? (MIP-2?) in culture supernatants was determined using a sandwich ELISA. The MIP-2? effect on the expression of GLT-1 was measured by quantitative RT-PCR, flow cytometric analysis or western blot assay. Detergent-resistant membranes from astrocytes were isolated on the basis of their ability to float in density gradients. Raft-containing fractions were tracked by the enrichment of caveolin-1 and the dendritic lipid raft marker, flotillin-1. Cell viability was determined by measuring either the leakage of lactate dehydrogenase or the reduction of 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide by viable cells and confirmed by visual inspection.The production of the chemokine MIP-2? by mouse cortical astrocytes increased significantly after stimulation with LPS or TNF-? in vitro. Astrocytes over-expressing MIP-2? down-regulated the expression of GLT-1 at the mRNA and protein level and caused redistribution of GLT-1 out of the lipid rafts that mediate glutamate uptake. We used pharmacological inhibitors to identify the downstream signaling pathways underlying MIP-2? activity. We also found complementary results by knocking down MIP-2? activity in astrocytes with MIP-2? small interfering RNA (siRNA). MIP-2? overexpression in astrocytes enhanced the neuronal toxicity of glutamate by decreasing GLT-1 activity, but MIP-2? itself was not toxic to neurons.These results suggest that MIP-2? mediates the pathogenesis of central nervous system disorders associated with neutrophil infiltration in the brain and decreased GLT-1 activity.

Dataset Information

Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes.

Publications

Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes.

Similar Datasets

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