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51	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 January 2010 (has links) No / 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. 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 Spectrometry Fluorescence Tumor necrosis factor-alpha Pharmacology p38 mitogen-activated protein kinases REF 2014

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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