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 Galpha(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 Galpha(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, Galpha(q/11) and PLC, and that the released ATP or ectopically converted ADP may in turn cause membrane ruffling via P2Y(12) receptors and Galpha(i/o) activation, and BDNF expression via activation of P2X(4) receptors.
Fujita
Ryousuke
R
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Bunkyo-machi, Nagasaki, Japan.
Ma
Yan
Y
Ueda
Hiroshi
H
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D022081:Cell Surface Extensions / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008246:Lysophospholipids / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008855:Microscopy, Electron, Scanning; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D049368:Receptors, Lysophosphatidic Acid / Q000187:drug effects / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D058848:Receptors, Purinergic P2X4; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D008246:Lysophospholipids; C548228:P2rx4 protein, rat; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C032881:lysophosphatidic acid