P2X7 receptors control 2-arachidonoylglycerol production by microglial cells.

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: Walter L
Zeitschrift: Proceedings of the National Academy of Sciences of the United States of America
Jahr der Veröffentlichung: 2004
Band: 101
Heftnummer: 9
Seitenbereich: 3214-9
ISSN: 0027-8424
eISSN: 1091-6490


Abstract


Endogenous cannabinoid ligands (endocannabinoids) produced by neurons, astrocytes, and microglial cells activate cannabinoid receptors, the molecular target for marijuana's bioactive ingredient Delta(9)-tetrahydrocannabinol. The molecular mechanism underlying the production of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), is unclear. A prevalent hypothesis proposes that activation of metabotropic receptors coupled to the phosphatidylinositol-specific phospholipase C and diacylglycerol (DG) lipase pathway will systematically lead to increases in 2-AG production. Here, we show that ATP increases 2-AG production by cultured microglial cells in a phosphatidylinositol-specific phospholipase C and DG lipase-dependent manner. However, efficacious activation of metabotropic P2Y purinergic receptors coupled to phosphatidylinositol-specific phospholipase C does not increase 2-AG production. This suggests that ionotropic, and not metabotropic, purinergic receptors control 2-AG production at an unexpected enzymatic step of its metabolic pathway. We show that activation of P2X(7) ionotropic receptors, which are highly permeable to calcium, is necessary and sufficient to increase 2-AG production in microglial cells. We also show that the sustained rise in intracellular calcium induced by activation of P2X(7) receptors directly increases DG lipase activity while inhibiting the activity of monoacylglycerol lipase, the enzyme that degrades 2-AG. This inverse sensitivity of DG lipase and monoacylglycerol lipase to calcium constitutes an original and efficient modality for sustained accumulation of 2-AG. Because prolonged increases in 2-AG amounts in brain parenchyma are thought to orchestrate neuroinflammation, the enzymatic steps involved in 2-AG synthesis and degradation by microglial cells constitute appealing targets for therapy aimed at controlling exacerbated neuroinflammation.



FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Walter, Lisa Dr.
Lehrstuhl für Informatik 14 (Maschinelles Lernen und Datenanalytik)

Zuletzt aktualisiert 2019-06-08 um 09:02