Transportable and Non-transportable Inhibitors of L-glutamate Uptake Produce Astrocytic Stellation and Increase EAAT2 Cell Surface Expression

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2010 Feb 10

PMID 20143158

Citations 8

Authors

Chew L Lau

Philip M Beart

Ross D OShea

Affiliations

Soon will be listed here.

Abstract

Astrocytic excitatory amino acid transporters (EAATs) regulate excitatory transmission and limit excitotoxicity. Evidence for a functional interface between EAATs and glial fibrillary acidic protein (GFAP) relevant to astrocytic morphology led to investigations of actions of transportable (D-Aspartate (D-Asp) and (2S,3S,4R)-2-(carboxycyclopropyl)glycine (L-CCG-III)) and non-transportable (DL-threo-beta-benzyloxyaspartate (DL-TBOA)) inhibitors of Glu uptake in murine astrocytes. D-Asp (1 mM), L-CCG-III (0.5 mM) and DL-TBOA (0.5 mM) produced time-dependent (24-72 h) reductions in (3)[H]D-Asp uptake (approximately 30-70%) with little or no gliotoxicity. All drugs induced a profound change in phenotype from cobblestone to stellate morphology and image analysis revealed increases in the intensity of GFAP immunolabelling for L-CCG-III and DL-TBOA. Cytochemistry indicated localized changes in F-actin distribution. Cell surface expression of EAAT2, but not EAAT1, was elevated at 72 h. Blockade of Glu uptake by both types of EAAT inhibitor exerts longer-term effects on astrocytic morphology and a compensatory homeostatic rise in EAAT2 abundance.

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References

Robinson M . Regulated trafficking of neurotransmitter transporters: common notes but different melodies. J Neurochem. 2002; 80(1):1-11. DOI: 10.1046/j.0022-3042.2001.00698.x. View

Hughes E, Maguire J, McMinn M, Scholz R, Sutherland M . Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking. Brain Res Mol Brain Res. 2004; 124(2):114-23. DOI: 10.1016/j.molbrainres.2004.02.021. View

Pekny M, Nilsson M . Astrocyte activation and reactive gliosis. Glia. 2005; 50(4):427-434. DOI: 10.1002/glia.20207. View

Maragakis N, Rothstein J . Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol. 2006; 2(12):679-89. DOI: 10.1038/ncpneuro0355. View

Cahoy J, Emery B, Kaushal A, Foo L, Zamanian J, Christopherson K . A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008; 28(1):264-78. PMC: 6671143. DOI: 10.1523/JNEUROSCI.4178-07.2008. View

Beart P, OShea R . Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol. 2006; 150(1):5-17. PMC: 2013845. DOI: 10.1038/sj.bjp.0706949. View

Zhou J, Sutherland M . Glutamate transporter cluster formation in astrocytic processes regulates glutamate uptake activity. J Neurosci. 2004; 24(28):6301-6. PMC: 6729534. DOI: 10.1523/JNEUROSCI.1404-04.2004. View

OShea R, Fodera M, Aprico K, Dehnes Y, Danbolt N, Crawford D . Evaluation of drugs acting at glutamate transporters in organotypic hippocampal cultures: new evidence on substrates and blockers in excitotoxicity. Neurochem Res. 2002; 27(1-2):5-13. DOI: 10.1023/a:1014813518604. View

Ridet J, Malhotra S, Privat A, Gage F . Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1998; 20(12):570-7. DOI: 10.1016/s0166-2236(97)01139-9. View

10.

Schlag B, Vondrasek J, Munir M, Kalandadze A, Zelenaia O, Rothstein J . Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol Pharmacol. 1998; 53(3):355-69. DOI: 10.1124/mol.53.3.355. View

11.

Kuhn T, Meberg P, Brown M, Bernstein B, Minamide L, Jensen J . Regulating actin dynamics in neuronal growth cones by ADF/cofilin and rho family GTPases. J Neurobiol. 2000; 44(2):126-44. View

12.

Bridges R, Esslinger C . The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol Ther. 2005; 107(3):271-85. DOI: 10.1016/j.pharmthera.2005.01.002. View

13.

Sheldon A, Robinson M . The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int. 2007; 51(6-7):333-55. PMC: 2075474. DOI: 10.1016/j.neuint.2007.03.012. View

14.

Shobha K, Vijayalakshmi K, Alladi P, Nalini A, Sathyaprabha T, Raju T . Altered in-vitro and in-vivo expression of glial glutamate transporter-1 following exposure to cerebrospinal fluid of amyotrophic lateral sclerosis patients. J Neurol Sci. 2007; 254(1-2):9-16. DOI: 10.1016/j.jns.2006.12.004. View

15.

Zagami C, OShea R, Lau C, Cheema S, Beart P . Regulation of glutamate transporters in astrocytes: evidence for a relationship between transporter expression and astrocytic phenotype. Neurotox Res. 2005; 7(1-2):143-9. DOI: 10.1007/BF03033783. View

16.

Zagami C, Beart P, Wallis N, Nagley P, OShea R . Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis. Glia. 2008; 57(2):119-35. DOI: 10.1002/glia.20739. View

17.

Davies L, Johnston G . Uptake and release of D- and L-aspartate by rat brain slices. J Neurochem. 1976; 26(5):1007-14. DOI: 10.1111/j.1471-4159.1976.tb06485.x. View

18.

Regan M, Huang Y, Kim Y, Dykes-Hoberg M, Jin L, Watkins A . Variations in promoter activity reveal a differential expression and physiology of glutamate transporters by glia in the developing and mature CNS. J Neurosci. 2007; 27(25):6607-19. PMC: 6672708. DOI: 10.1523/JNEUROSCI.0790-07.2007. View

19.

Marcaggi P, Attwell D . Role of glial amino acid transporters in synaptic transmission and brain energetics. Glia. 2004; 47(3):217-225. DOI: 10.1002/glia.20027. View

20.

Guiramand J, Martin A, De Jesus Ferreira M, Cohen-Solal C, Vignes M, Recasens M . Gliotoxicity in hippocampal cultures is induced by transportable, but not by nontransportable, glutamate uptake inhibitors. J Neurosci Res. 2005; 81(2):199-207. DOI: 10.1002/jnr.20557. View