NDLI: The Glutamate Aspartate Transporter (GLAST) Mediates l-Glutamate-Stimulated Ascorbate-Release Via Swelling-Activated Anion Channels in Cultured Neonatal Rodent Astrocytes

Content Provider	Springer Nature Link
Author	Lane, Darius J. R. Lawen, Alfons
Copyright Year	2012
Abstract	Vitamin C (ascorbate) plays important neuroprotective and neuromodulatory roles in the mammalian brain. Astrocytes are crucially involved in brain ascorbate homeostasis and may assist in regenerating extracellular ascorbate from its oxidised forms. Ascorbate accumulated by astrocytes can be released rapidly by a process that is stimulated by the excitatory amino acid, l-glutamate. This process is thought to be neuroprotective against excitotoxicity. Although of potential clinical interest, the mechanism of this stimulated ascorbate-release remains unknown. Here, we report that primary cultures of mouse and rat astrocytes release ascorbate following initial uptake of dehydroascorbate and accumulation of intracellular ascorbate. Ascorbate-release was not due to cellular lysis, as assessed by cellular release of the cytosolic enzyme lactate dehydrogenase, and was stimulated by l-glutamate and l-aspartate, but not the non-excitatory amino acid l-glutamine. This stimulation was due to glutamate-induced cellular swelling, as it was both attenuated by hypertonic and emulated by hypotonic media. Glutamate-stimulated ascorbate-release was also sensitive to inhibitors of volume-sensitive anion channels, suggesting that the latter may provide the conduit for ascorbate efflux. Glutamate-stimulated ascorbate-release was not recapitulated by selective agonists of either ionotropic or group I metabotropic glutamate receptors, but was completely blocked by either of two compounds, TFB-TBOA and UCPH-101, which non-selectively and selectively inhibit the glial Na$^{+}$-dependent excitatory amino acid transporter, GLAST, respectively. These results suggest that an impairment of astrocytic ascorbate-release may exacerbate neuronal dysfunction in neurodegenerative disorders and acute brain injury in which excitotoxicity and/or GLAST deregulation have been implicated.
Starting Page	107
Ending Page	119
Page Count	13
File Format	PDF
ISSN	10859195
Journal	Cell Biochemistry and Biophysics
Volume Number	65
Issue Number	2
e-ISSN	15590283
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-08-12
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Cell swelling EAAT1/GLAST Glutamate excitotoxicity Vitamin C UCPH-101 VSOAC/VRAC Biochemistry Pharmacology/Toxicology Biotechnology Cell Biology Biophysics and Biological Physics
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Biochemistry Biophysics

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