RT Journal Article
SR Electronic
T1 ATP Induces a Rapid and Pronounced Increase in 2-Arachidonoylglycerol Production by Astrocytes, a Response Limited by Monoacylglycerol Lipase
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8068
OP 8074
DO 10.1523/JNEUROSCI.2419-04.2004
VO 24
IS 37
A1 Lisa Walter
A1 Thien Dinh
A1 Nephi Stella
YR 2004
UL http://www.jneurosci.org/content/24/37/8068.abstract
AB 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 P2X7 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.