Platelet-activating factor in the modulation of excitatory amino acid neurotransmitter release and of gene expression.
Selective phospholipids of synaptic membranes are reservoirs for lipid second messengers. 1-Alkyl-2 arachidonoyl glycero-3-phosphocholine is hydrolyzed by phospholipase A2 (PLA2) into two products: lyso-PAF, which is transacetylated to yield platelet-activating factor (PAF), and free arachidonic acid (20:4), which can undergo oxidative metabolism to eicosanoids. Alternative pathways of PAF synthesis, such as CoA-independent transacylase and the de novo route of synthesis, remain to be explored and compared to the PLA2-dependent route. At low concentrations, PAF is a retrograde messenger of LTP in CA1 hippocampal neurons, and is also a memory enhancer in inhibitor avoidance tasks. PAF enhances excitatory amino acid release in synaptic pairs from primary hippocampal cultures by a presynaptic mechanism. Ischemia and convulsions activate synaptic PLA2. Thus, increased concentrations of PAF promote massive glutamate exocytosis, glutamate receptor activation, and elevated intracellular calcium levels in target cells. As a result, calcium-sensitive cascades are affected. PAF thus had dual roles as a lipid mediator: under physiological conditions it modulates neurotransmitter release, but at high concentrations it becomes neurotoxic. Through an intracellular high affinity binding site, PAF activates the expression of immediate-early genes. Some of these genes encode transcription factors (e.g. zif-268, c-fos), and others encode enzymes (COX-2 or inducible prostaglandin synthase). PAF also activates the expression of metalloproteinases which participate in the remodeling of the extracellular matrix. These effects have been studied in cells in culture as well as in the brain. A PAF antagonist specific for the intracellular binding site inhibits COX-2 expression elicited by a single electroconvulsive shock or vasogenic edema. COX-1, the constitutive prostaglandin synthase, is not induced and is unaffected by the antagonist. Most of the cerebral induction occurs in the hippocampus and results from transcriptional activation. PAF mediated gene expression may be involved in neural plasticity as well as in pathophysiological conditions in which the neural tissue activates repair-injury pathways.
Bazan
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Louisiana State University Medical Center School of Medicine, LSU Eye Center, New Orleans 70112, USA.
Allan
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G
D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology*; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D009473:Neuronal Plasticity / Q000502:physiology; D018377:Neurotransmitter Agents / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D018377:Neurotransmitter Agents; D010972:Platelet Activating Factor