Lysophosphatidic acid-induced membrane ruffling and brain-derived neurotrophic factor gene expression are mediated by ATP release in primary microglia

We examined the effects of lysophosphatidic acid (LPA) on microglia, which may play an important role in the development and maintenance of neuropathic pain. LPA caused membrane ruffling as detected by scanning electron microscopy, and increased the expression of brain-derived neurotrophic factor (BDNF) in a primary culture of rat microglia, which express LPA(3), but not LPA(1) or LPA(2) receptors. These actions were inhibited by a G alpha(q/11)-antisense oligodeoxynucleotide (AS-ODN), U73122, an inhibitor of phospholipase C (PLC), and apyrase, which specifically degrades ATP and ADP. When ATP release was measured using a luciferin-luciferase bioluminescence assay, LPA was shown to increase it in an LPA(3) and PLC inhibitor-reversible manner. However, LPA-induced ATP release was also blocked by the G alpha(q/11) AS-ODN, but not by pertussis toxin. These results suggest that LPA induces the release of ATP from rat primary cultured microglia via the LPA(3) receptor, G alpha(q/11) and PLC, and that the released ATP or ectopically converted ADP may in turn cause membrane ruffling via P2Y(12) receptors and G alpha(i/o) activation, and BDNF expression via activation of P2X(4) receptors.