Modulation of the glutamate-evoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A2


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Modulation of the glutamate-evoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A2
Journal of Neuroscience
Stella  N., Pellerin  L., Magistretti  P. J.
0270-6474 (Print)
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5 Pt 1
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: May
Excitatory synaptic transmission is associated with changes in both extracellular and intracellular pH. Using mouse cortical neurons in primary cultures, we studied the sensitivity of glutamate-evoked release of 3H-arachidonic acid (3H-AA) to changes in extracellular pH (pHo) and related intracellular pH (pHi). As pHo was shifted from 7.2 to 7.8, the glutamate-evoked release of 3H-AA was enhanced by approximately threefold. The effect of alkaline pHo on the glutamate response was rapid, becoming significant within 2 min. 3H-AA release, evoked by both NMDA and kainate, was also enhanced by pHo alkalinization. NMDA- and kainate-induced increase in free intracellular Ca2+ was unaffected by changing pHo from 7.2 to 7.8, indicating that the receptor-induced Ca2+ influx is not responsible for the pHo sensitivity of the glutamate-evoked release of 3H-AA. Alkalinization of pHi obtained by incubating neurons in the presence of HCO3- or NH4 enhanced the glutamate-evoked release of 3H-AA, while pHi acidification obtained by blockade of Na+/H+ and Cl-/HCO3- exchangers decreased the glutamate response. Membrane-bound phospholipase A2 (mPLA2) activity was stimulated by Ca2+ in a pH-dependent manner, increasing its activity as pH was shifted from 7.2 to 7.8. This pH profile corresponds to the pH profile of the glutamate-, NMDA- and kainate-evoked release of 3H-AA. Taken together, these results indicate that the glutamate-evoked release of 3H-AA may be mediated by the pH-sensitive mPLA2. Since excitatory neurotransmission mediated by glutamate results in both pHo and pHi changes and since AA enhances glutamatergic neurotransmission at both pre- and postsynaptic levels, the data reported here reveals a possible molecular mechanism whereby glutamate can modulate its own signalling efficacy in a pH-dependent manner by regulating the release of AA.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology Amiloride/pharmacology Ammonium Chloride/pharmacology Animals Arachidonic Acid/*metabolism Calcium/metabolism Cell Membrane/enzymology Cell Survival Cells, Cultured Cerebral Cortex/cytology/*metabolism Dizocilpine Maleate/pharmacology Embryo Female Glutamic Acid/*pharmacology Harmaline/pharmacology Hydrogen-Ion Concentration Immunohistochemistry Kainic Acid/pharmacology Kinetics Kynurenic Acid/pharmacology Mice N-Methylaspartate/pharmacology Neurons/cytology/drug effects/*metabolism Phospholipases A/*metabolism Pregnancy Time Factors Tritium
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