Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 37, Pages 8068-8074Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2419-04.2004
Keywords
2-AG; ATP; lipase; cannabinoid; astrocyte; glia
Categories
Funding
- NIDA NIH HHS [DA12447, R01 DA012447, DA14486, R01 DA014486] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007270, T32 GM07270] Funding Source: Medline
- NINDS NIH HHS [NS044337, R01 NS044337] Funding Source: Medline
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The cytoplasm of neural cells contain millimolar amounts of ATP, which flood the extracellular space after injury, activating purinergic receptors expressed by glial cells and increasing gliotransmitter production. These gliotransmitters, which are thought to orchestrate neuroinflammation, remain widely uncharacterized. Recently, we showed that microglial cells produce 2-arachidonoylglycerol (2-AG), an endocannabinoid known to prevent the propagation of harmful neuroinflammation, and that ATP increases this production by threefold at 2.5 min ( Witting et al., 2004). Here we show that ATP increases 2-AG production from mouse astrocytes in culture, a response that is more rapid (i.e., significant within 10 sec) and pronounced (i.e., 60- fold increase at 2.5 min) than any stimulus-induced increase in endocannabinoid production reported thus far. Increased 2-AG production from astrocytes requires millimolar amounts of ATP, activation of purinergic P2X(7) receptors, sustained rise in intracellular calcium, and diacylglycerol lipase activity. Furthermore, we show that astrocytes express monoacylglycerol lipase (MGL), the main hydrolyzing enzyme of 2-AG, the pharmacological inhibition of which potentiates the ATP-induced 2-AG production ( up to 113-fold of basal 2-AG production at 2.5 min). Our results show that ATP greatly increases, and MGL limits, 2-AG production from astrocytes. We propose that 2-AG may function as a gliotransmitter, with MGL inhibitors potentiating this production and possibly restraining the propagation of harmful neuroinflammation.
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