LYSOPHOSPHATIDIC ACID-INDUCED PROLIFERATION-RELATED SIGNALS IN ASTROCYTES

Lysophosphatidic acid (LPA) is a potent lipid biomediator that is like ly to have diverse roles in the brain. Thus, LPA-induced events in ast rocytes were defined, As little as 1 nM LPA induced a rapid increase i n the concentration of intracellular free calcium ([Ca2+](i)) in astro cytes from neonatal rat brains. This increase was followed by a slow r eturn to the basal level, Intracellular calcium stores were important for the initial rise in [Ca2+](i), whereas the influx of extracellular calcium contributed significantly to the extended elevation of [Ca2+] (i), LPA treatment also resulted in increases in lipid peroxidation an d DNA synthesis, These increases in [Ca2+](i), lipid peroxidation, and DNA synthesis were inhibited by pretreatment of cells with pertussis toxin or H7, a serine/threonine protein kinase inhibitor. Moreover, th e LPA-induced increase in [Ca2+](i) was inhibited by a protein kinase C inhibitor, Ro 31-8220, and a calcium-dependent protein kinase C inhi bitor, Go 6976. The increase in [Ca2+](i) was important for the LPA-in duced increase in lipid peroxidation, whereas the antioxidant, propyl gallate, inhibited the LPA-stimulated increases in lipid peroxidation and DNA synthesis, In contrast, pertussis toxin, H7, and propyl gallat e had no effect on LPA-induced inhibition of glutamate uptake, Thus, L PA appears to signal via at least two distinctive mechanisms in astroc ytes. One is a novel pathway, namely, activation of a pertussis toxin- sensitive G protein and participation of a protein kinase, leading to sequential increases in [Ca2+](i), lipid peroxidation, and DNA synthes is.