ATP stimulation of Ca2+‐dependent plasminogen release from cultured microglia

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Abstract
ATP (10–100 μm), but not glutamate (100 μm), stimulated the release of plasminogen from microglia in a concentration‐dependent manner during a 10 min stimulation. However, neither ATP (100 μm) nor glutamate (100 μm) stimulated the release of NO. A one hour pretreatment with BAPTA‐AM (200 μm), which is metabolized in the cytosol to BAPTA (an intracellular Ca2+ chelator), completely inhibited the plasminogen release evoked by ATP (100 μm). The Ca2+ ionophore A23187 induced plasminogen release in a concentration‐dependent manner (0.3 μm to 10 μm). ATP induced a transient increase in the intracellular calcium concentration ([Ca2+]i) in a concentration‐dependent manner which was very similar to the ATP‐evoked plasminogen release, whereas glutamate (100 μm) had no effect on [Ca2+]i (70 out of 70 cells) in microglial cells. A second application of ATP (100 μm) stimulated an increase in [Ca2+]i similar to that of the first application (21 out of 21 cells). The ATP‐evoked increase in [Ca2+]i was totally dependent on extracellular Ca2+, 2‐Methylthio ATP was active (7 out of 7 cells), but α,β‐methylene ATP was inactive (7 out of 7 cells) at inducing an increase in [Ca2+]i. Suramin (100 μm) was shown not to inhibit the ATP‐evoked increase in [Ca2+]i (20 out of 20 cells). 2′‐ and 3′‐O‐(4‐Benzoylbenzoyl)‐adenosine 5′‐triphosphate (BzATP), a selective agonist of P2X7 receptors, evoked a long‐lasting increase in [Ca2+]i even at 1 μm, a concentration at which ATP did not evoke the increase. One hour pretreatment with adenosine 5′‐triphosphate‐2′, 3′‐dialdehyde (oxidized ATP, 100 μm), a selective antagonist of P2X7 receptors, blocked the increase in [Ca2+]i induced by ATP (10 and 100 μm). These data suggest that ATP may transit information from neurones to microglia, resulting in an increase in [Ca2+]i via the ionotropic P2X7 receptor which stimulates the release of plasminogen from the microglia. British Journal of Pharmacology (1998) 123, 1304–1310; doi:10.1038/sj.bjp.0701732