Lysophosphatidic acid-induced proliferation-related signals in astrocytes

Lysophosphatidic acid (LPA) is a potent lipid biomediator that is likely to have diverse roles in the brain. Thus, LPA-induced events in astrocytes were defined. As little as 1 nM LPA induced a rapid increase in the concentration of intracellular free calcium ([Ca²⁺](i)) in astrocytes from neonatal rat brains. This increase was followed by a slow return 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 and 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, the LPA-induced increase in [Ca²⁺](i) was inhibited by a protein kinase C inhibitor, Ro 31-8220, and a calcium- dependent protein kinase C inhibitor, Go 6976. The increase in [Ca²⁺](i) was important for the LPA-induced 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 gallate had no effect on LPA-induced inhibition of glutamate uptake. Thus, LPA appears to signal via at least two distinctive mechanisms in astrocytes. 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 synthesis.