Tumour necrosis factor alpha induces rapid reduction in AMPA receptor-mediated calcium entry in motor neurones by increasing cell surface expression of the GluR2 subunit: relevance to neurodegeneration
Rainey-Smith, S.R. Andersson, D.A. Williams, R.J. Rattray, Marcus
Rainey-Smith, S.R.
Andersson, D.A.
Williams, R.J.
Rattray, Marcus
Publication Date
2010
End of Embargo
Supervisor
Keywords
Animals, Biotinylation, Blotting, Western, Calcium, Metabolism, Calcium signaling, Drug effects, Cell survival, Drug effects, Cells, Cultured, Excitatory amino acid agonists, Toxicity, Female, Fluorescent antibody technique, Kainic acid, Antagonists & inhibitors, Toxicity, Mice, Motor neurons, Drug effects, Nerve degeneration, Pathology, Neuroprotective agents, Phosphatidylinositol 3-Kinases, Pregnancy, Receptors, AMPA, Antagonists & inhibitors, Biosynthesis, Genetics, Receptors, Cell surface, Biosynthesis, Receptors, Tumor necrosis factor, Drug effects, Reverse transcriptase polymerase chain reaction, Spectrometry, Fluorescence, Tumor necrosis factor-alpha, Pharmacology, p38 mitogen-activated protein kinases, REF 2014
Rights
Peer-Reviewed
Open Access status
closedAccess
Accepted for publication
Institution
Department
Awarded
Embargo end date
Collections
Additional title
Abstract
The alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) subunit GluR2, which regulates excitotoxicity and the inflammatory cytokine tumour necrosis factor alpha (TNFalpha) have both been implicated in motor neurone vulnerability in amyotrophic lateral sclerosis/motor neurone disease. TNFalpha has been reported to increase cell surface expression of AMPAR subunits to increase synaptic strength and enhance excitotoxicity, but whether this mechanism occurs in motor neurones is unknown. We used primary cultures of mouse motor neurones and cortical neurones to examine the interaction between TNFalpha receptor activation, GluR2 availability, AMPAR-mediated calcium entry and susceptibility to excitotoxicity. Short exposure to a physiologically relevant concentration of TNFalpha (10 ng/mL, 15 min) caused a marked redistribution of both GluR1 and GluR2 to the cell surface as determined by cell surface biotinylation and immunofluorescence. Using fura-2-acetoxymethyl ester microfluorimetry, we showed that exposure to TNFalpha caused a rapid reduction in the peak amplitude of AMPA-mediated calcium entry in a PI3-kinase and p38 kinase-dependent manner, consistent with increased insertion of GluR2-containing AMPAR into the plasma membrane. This resulted in a protection of motor neurones against kainate-induced cell death. Our data therefore, suggest that TNFalpha acts primarily as a physiological regulator of synaptic activity in motor neurones rather than a pathological drive in amyotrophic lateral sclerosis.
Version
No full-text in the repository
Citation
Rainey-Smith, S. R., Andersson, D. A., Williams, R. J., Rattray, M. (2010) Tumour necrosis factor alpha induces rapid reduction in AMPA receptor-mediated calcium entry in motor neurones by increasing cell surface expression of the GluR2 subunit: relevance to neurodegeneration. Journal of Neurochemistry, 113(3), 692-703.
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article