Pleiotropic Effects of Lysophosphatidic Acid on Striatal Astrocytes

Lysophosphatidic acid (LPA) is a potent lipid mediator that is likely involved in diverse functions in the brain. Several recent studies have suggested that astrocytes are important target cells for LPA. In the present study, we have identified the signal transduction pathways activated following LPA stimulation in mouse striatal astrocytes in primary culture. In cells prelabeled with myo-[3H]inositol, LPA stimulated the formation of [3H]inositol phosphates (EC50 = 0.7 microM). This effect was reproduced neither by other lysophospholipids nor by phosphatidic acid. Astrocyte pretreatment with pertussis toxin partially abolished this LPA response indicating the involvement of a Gi/Go protein. In [3H]adenine-prelabeled cells, LPA strongly inhibited the formation of [3H]cyclic AMP induced by forskolin (EC(50) = 0.3 microM) and by isoproterenol and PACAP-38. These inhibitory effects were strongly reduced by pertussis toxin treatment. Although with a lesser potency (EC50 = 5 microM), LPA also stimulated the release of [3H]arachidonic acid from [3H]arachidonic acid-prelabeled astrocytes. This latter effect was totally inhibited by mepacrine, did not involve a pertussis toxin-sensitive G protein, and was highly dependent on external calcium. LPA also stimulated the activity of both extracellular signal-regulated kinases (Erk) Erk1 and Erk2 by a mechanism involving a Gi/Go protein. Surprisingly, in contrast to that observed in fibroblasts, LPA was totally ineffective in stimulating DNA synthesis. These results provide additional evidence in favor of an important physiological role of LPA in the astrocytic functions.