Lysophosphatidic acid induces a sustained elevation of neuronal intracellular calcium

Lysophosphatidic acid (LPA) is a lipid biomediator enriched in the brain. A novel LPA-induced response in rat hippocampal neurons is described herein, namely, a rapid and sustained elevation in the concentration of free intracellular calcium ([Ca²⁺](i)). This increase is specific, in that the related lipids phosphatidic acid and lysophosphatidylcholine did not induce an alteration in [Ca²⁺](i). Moreover, consistent with a receptor-mediated process, there was no further increase in [Ca²⁺](i) after a second addition of LPA. The LPA-induced increase in [Ca²⁺](i) required extracellular calcium. However, studies with Cd²⁺, Ni²⁺, and nifedipine and nystatin- perforated patch clamp analyses did not indicate involvement of voltage- gated calcium channels in the LPA-induced response. In contrast, glutamate appears to have a significant role in the LPA-induced increase in [Ca²⁺](i), because this increase was inhibited by NMDA receptor antagonists and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonists. Thus, LPA treatment may result in an increased extracellular glutamate concentration that could stimulate AMPA/kainate receptors and thereby alleviate the Mg²⁺ block of the NMDA receptors and lead to glutamate stimulation of an influx of calcium via NMDA receptors.