Tumor necrosis factor alpha increases cytosolic calcium responses to AMPA and KCl in primary cultures of rat hippocampal neurons.
Acute behavioral effects of tumor necrosis factor alpha (TNFalpha) have been previously reported, however the cellular basis for these actions are unknown. To address this issue we examined the effects of TNFalpha on AMPA- and depolarization-induced changes in cytosolic Ca(2+) in cultured hippocampal neurons. Single cell Ca(2+) levels were determined with the fluorescent calcium indicator fura-2. TNFalpha caused an up-regulation of AMPA (10 microM)- and depolarization (55 mM KCl)-induced Ca(2+) responses. This effect occurred within a window of concentrations (1 and 10 ng/ml but not 0.1 or 100 ng/ml) and times (3 and 6 h but not 1 and 24 h). The effect was dependent upon protein synthesis (blocked by cycloheximide) and was prevented by the soluble TNF receptor and by a soluble TNF receptor fragment. Treatment with the soluble TNF receptor fragment also caused a decrease in the basal response. The TNFalpha treatment protocols did not appear to produce any toxicity to the neurons. Results are consistent with the hypothesis that TNFalpha regulates proteins known to be involved in neuronal communication (AMPA receptors) and cell regulation (voltage-dependent calcium channels) in a relatively rapid period of time (a few hours). These actions may be related to the behavioral effects produced by TNFalpha that occur within this time frame.
De
Alok
A
Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, College of Veterinary Medicine, Washington State University, 205 Wegner Hall, Pullman, WA 99164-6520, USA.
Krueger
James M
JM
Simasko
Steven M
SM
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D060848:Agatoxins; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016257:Fura-2 / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D060848:Agatoxins; D002121:Calcium Channel Blockers; D018683:Excitatory Amino Acid Agents; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D013111:Spider Venoms; D014409:Tumor Necrosis Factor-alpha; C083855:omega-agatoxin-Aa4b; D011189:Potassium Chloride; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D020866:omega-Conotoxin GVIA; D003513:Cycloheximide; D002118:Calcium; D016257:Fura-2