Glutamate signalling and secretory phospholipase A2 modulate the release of arachidonic acid from neuronal membranes.
The lipid mediators generated by phospholipases A(2) (PLA(2)), free arachidonic acid (AA), eicosanoids, and platelet-activating factor, modulate neuronal activity; when overproduced, some of them become potent neurotoxins. We have shown, using primary cortical neuron cultures, that glutamate and secretory PLA(2) (sPLA(2)) from bee venom (bv sPLA(2)) and Taipan snake venom (OS2) elicit synergy in inducing neuronal cell death. Low concentrations of sPLA(2) are selective ligands of cell-surface sPLA(2) receptors. We investigated which neuronal arachidonoyl phospholipids are targeted by glutamate-activated cytosolic calcium-dependent PLA(2) (cPLA(2)) and by sPLA(2). Treatment of (3)H-AA-labeled cortical neurons with mildly toxic concentrations of sPLA(2) (25 ng/ml, 1.78 nM) for 45 min resulted in a two- to threefold higher loss of (3)H-AA from phosphatidylcholine (PC) than from phosphatidylethanolamine (PE) and in minor changes in other phospholipids. A similar profile, although of greater magnitude, was observed 20 hr posttreatment. Glutamate (80 microM) induced much less mobilization of (3)H-AA than did sPLA(2) and resulted in a threefold greater degradation of (3)H-AA PE than of (3)H-AA PC by 20 hr posttreatment. Combining sPLA(2) and glutamate resulted in a greater degradation of PC and PE, and the N-methyl-D-aspartate receptor antagonist MK-801 only blocked glutamate effects. Thus, activation of the arachidonate cascade induced by glutamate and sPLA(2) under experimental conditions that lead to neuronal cell death involves the hydrolysis of different (perhaps partially overlapping) cellular phospholipid pools.
Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Elena B
EB
Rodriguez De Turco
Fannie R
FR
Jackson
Mark A
MA
DeCoster
Miriam
M
Kolko
Nicolas G
NG
Bazan
D000818:Animals; D016718:Arachidonic Acid / Q000493:pharmacokinetics*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018698:Glutamic Acid / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000493:pharmacokinetics; D010714:Phosphatidylethanolamines / Q000493:pharmacokinetics; D010741:Phospholipases A / Q000378:metabolism / Q000494:pharmacology*; D054467:Phospholipases A2; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014316:Tritium
D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D014316:Tritium; D016718:Arachidonic Acid; D018698:Glutamic Acid; D010741:Phospholipases A; D054467:Phospholipases A2