Modification of glutamate receptors by phospholipase A2: its role in adaptive neural plasticity

Abstract

Long-term potentiation (LTP) and long-term depression (LTD) are two electrophysiological models that have been studied extensively in recent years as they may represent basic mechanisms in many neuronal networks to store certain types of information. In several brain regions, it has been shown that these two forms of synaptic plasticity require sufficient dendritic depolarization, with the amplitude of the calcium signal being crucial for the generation of either LTP or LTD. The rise in calcium concentration mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to stimulate various calcium-dependent enzymatic processes that could convert the induction signal into long-lasting changes in synaptic structure; protein kinases and phosphatases have so far been considered predominantly with regard to LTP and LTD formation. According to several lines of experimental evidence, changes in synaptic function observed with LTP and LTD are thought to be the result of modifications of postsynaptic currents mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. Moreover, it has become apparent recently that activation of the calcium-dependent enzyme phospholipase A2 (PLA2) could be part of the molecular mechanisms involved in alterations of AMPA receptor properties during long-term changes in synaptic operation. In the present review, we will first describe the results that indicate a critical role of the phospholipases in regulating synaptic function. Next, sections will be devoted to the effects of PLA2 and phospholipids on the binding properties of glutamate receptors, and a revised biochemical model will be presented as an attempt to integrate the PLA2 enzyme into the mechanisms ( in particular kinases and phosphatases) that participate in adaptive neural plasticity. Finally, we will review data relevant to the issue of selective changes in AMPA binding after environmental enrichment and LTP.

Phospholipase A2 in the central nervous system

“…AA is regarded as a neuromodulator in the CNS, and PLA 2 is thought to have a role in neuronal plasticity (61). Neuronal excitation resulting from depolarization with high concentrations of potassium (62) and stimulation with excitatory neurotransmitter agonists such as ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (63), N-methyl-d-aspartic acid (NMDA) (64), and glutamate (65), as well as muscarinic cholinergic agonists (66), can stimulate AA release in neurons.…”

The Caveolin Scaffolding Domain Modifies 2-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate Receptor Binding Properties by Inhibiting Phospholipase A2 Activity

“…It has been proposed that during high frequency stimulation a large entry of calcium mediated by N-methyl-D-aspartate (NMDA) glutamate receptor activation might cause an increase in PLA 2 activity. The enzyme would augment AMPA receptor affinity by changing the lipid environment of AMPA receptors, thereby producing LTP (10). Recently, it has been reported that detergent-insoluble caveolin-rich membrane domains are markedly enriched in AMPA-type glutamate receptors (11), AA and PLA 2 (12,13), suggesting a possible role for PLA 2 in caveolae-dependent cellular functions.…”

Dysregulation of Phospholipid Metabolism in Synaptic Membranes and Their Role in Encephalopathy Forming After a Hemorrhagic Shock

“…The activation of both isoforms of phospholipase A 2 is partly the mechanism mediating the change of properties of AMPA-sensitive glutamate receptors, playing an important role in the modulation of neurotransmission [29,30]. It is possible also to note the role of phospholipase A 2 in enhancing the secretion of neurotransmitters in the nervous system, mediated by independent of Ca 2+ liberation of fatty acids (especially arachidonic) from the PLs of the synaptic membranes, which initiates the fusion of the mediator vesicles with the acceptor [31].…”