A study of the mechanism of the release of ATP from rat cortical astroglial cells evoked by activation of glutamate receptors

Glutamate and the selective agonists at ionotropic glutamate receptors N-me thyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMP A) and kainate release ATP from superfused primary cultures of rat cortical astrocytes. The mechanism of this release was investigated. The release of ATP elicited by N-methyl-D-aspartate and kainate was abolished or greatly reduced in the absence of external calcium as well as in the presence of ca dmium (1 mM) and nicardipine (10 mu M) The release of ATP elicited by AMPA, in contrast, was not changed by these interventions. The calcium ionophore ionomycin (5 mu M) released ATP in the presence but not in the absence of external calcium. No release was obtained with ol-latrotoxin. Of several co mpounds tested as potential blockers of ATP transporters or channels only g libenclamide (100 mu M) and diphenylamine-2-carboxylate (500 mu M), which b lock the cystic fibrosis transmembrane conductance regulator, caused any ch ange: both reduced the effect of AMPA without changing the effects of N-met hyl-D-aspartate and (only glibenclamide tested) kainate. Lithium (1 mM) abo lished the release of ATP evoked by glutamate and AMPA and significantly re duced the release evoked by N-methyl-D-aspartate and kainate. The three glu tamate receptor agonists did not increase the release of lactate dehydrogen ase. The results confirm the previous observation that activation of N-methyl-D- aspartate, AMPA and kainate receptors induces release of ATP from astrocyte s in culture. Two different mechanisms seem to be involved. The N-methyl-D- aspartate- and kainate-induced release of ATP requires an influx of calcium , is not due to neuron-like exocytosis, is not mediated by cystic fibrosis transmembrane conductance regulator or a mechanism regulated by cystic fibr osis transmembrane conductance regulator, and is reduced (by an unknown mec hanism) but not abolished by lithium. The AMPA-induced release does not req uire extracellular calcium, may be mediated by cystic fibrosis transmembran e conductance regulator or a mechanism regulated by cystic fibrosis transme mbrane conductance regulator, and is abolished (by an unknown mechanism) by lithium. The ability of astrocytes to both release ATP and respond to ATP suggests that ATP may act as an autocrine or paracrine messenger between th ese glial cells. (C) 1999 IBRO. Published by Elsevier Science Ltd.