GLUTAMATE-EVOKED RELEASE OF ARACHIDONIC-ACID FROM MOUSE-BRAIN ASTROCYTES

Brain astrocytes in primary culture from the rat or the mouse have bee n shown to possess ionotropic and metabotropic glutamatergic receptors . The activation of both types of receptors is responsible for a rise in the cytosolic concentration of calcium, while the stimulation of me tabotropic receptors induces the accumulation of inositol phosphates. In the present study, it is demonstrated that in striatal astrocytes f rom mouse embryos, glutamate evokes a release of arachidonic acid. The nonionotropic receptors involved in this effect appeared to be pharma cologically distinct from those coupled to phospholipase C: (1) glutam ate displayed different dose-response curves for the production of ino sitol phosphates (biphasic: EC(50) = 25 and 300 mu M) and the release of arachidonic acid (monophasic: EC(50) = 200 mu M); (2) L(+)-2-amino- 4-phosphonobutyric acid (AP4) only antagonized the glutamate-evoked re lease of arachidonic acid without altering the production of inositol phosphates; (3) when used at a concentration of 0.1 mM, quisqualate in duced a higher formation of inositol phosphates than glutamate (2 mM) while, in contrast to glutamate, it only weakly stimulated arachidonic acid release when used either at 0.1 mM or 1 mM. L(+)-2-amino-3-phosp honopropionic acid (AP3) suppressed both responses. The glutamate-evok ed release of arachidonic acid seems to be oppositely regulated by pro tein kinases A and C. Indeed, the stimulation of adenylate cyclase by the B-adrenergic agonist isoproterenol, vasoactive intestinal peptide, or pretreatment of striatal astrocytes with cholera toxin decreased t he glutamate-evoked release of arachidonic acid. In contrast, ATP, whi ch markedly stimulated inositol phosphate production, strongly potenti ated the glutamate-evoked release of arachidonic acid. An activation o f protein kinase C could be involved in this potentiation since it was reproduced by the phorbol ester phorbol 12-myristate 13-acetate (PMA) , and depressed by staurosporine or when protein kinase C was desensit ized by long-term pretreatment with PMA.