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The Journal of Neuroscience, March 15, 2001, 21(6):1975-1982
Extracellular ATP or ADP Induce Chemotaxis of Cultured Microglia through Gi/o-Coupled P2Y Receptors
Shizuyo Honda1, Yo Sasaki1, Keiko Ohsawa1, Yoshinori Imai1, Yasuko Nakamura1, Kazuhide Inoue2, and Shinichi Kohsaka1 1 Department of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan, and 2 Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
The initial microglial responses that occur after brain injury and in various neurological diseases are characterized by microglial accumulation in the affected sites of brain that results from the migration and proliferation of these cells. The early-phase signal responsible for this accumulation is likely to be transduced by rapidly diffusible factors. In this study, the possibility of ATP released from injured neurons and nerve terminals affecting cell motility was determined in rat primary cultured microglia. Extracellular ATP and ADP induced membrane ruffling and markedly enhanced chemokinesis in Boyden chamber assay. Further analyses using the Dunn chemotaxis chamber assay, which allows direct observation of cell movement, revealed that both ATP and ADP induced chemotaxis of microglia. The elimination of extracellular calcium or treatment with pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, suramin, or adenosine-3'-phosphate-5'-phosphosulfate did not inhibit ATP- or ADP-induced membrane ruffling, whereas AR-C69931MX or pertussis toxin treatments clearly did so. As an intracellular signaling molecule underlying these phenomena, the small G-protein Rac was activated by ATP and ADP stimulation, and its activation was also inhibited by pretreatment with pertussis toxin. These results strongly suggest that membrane ruffling and chemotaxis of microglia induced by ATP or ADP are mediated by Gi/o-coupled P2Y receptors.
Key words: microglia; ATP; ADP; membrane ruffling; chemotaxis; Gi/o-coupled P2Y receptors
Copyright © 2001 Society for Neuroscience 0270-6474/01/2161975-08$05.00/0
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