ReviewEndocannabinoid signaling in microglial cells
Section snippets
Cannabinoid receptors
At least five subtypes of CB receptors have been identified: the two cloned receptors (CB1 and CB2), GPR55, and two receptors that have been pharmacologically pinpointed but remain to be identified at the molecular level.
CB1 receptors are expressed throughout the brain by many different subtypes of neurons and at lower levels by other types of cells (Howlett et al., 2002, Matsuda et al., 1990, Tsou et al., 1998). In brain, they are most abundant in GABAergic interneurons, being between three
Endocannabinoid production, pharmacology and inactivation
In 1992, Raphael Mechoulam and coworkers identified arachidonoylethanolamide, which was named anandamide, as the first endogenous compound that binds to CB1 receptors with high affinity (Devane et al., 1992). Anandamide is considered a bona fide eCB because (I) it is produced by cells in an activity-dependent manner, (II) it activates CB1 and CB2 receptors and (III) it is enzymatically inactivated. Depolarization- and agonist-induced increase in anandamide production was initially shown in
Microglial cells
Microglia derive from the monocytic lineage, entering the developing brain before the establishment of a functional blood–brain barrier and distribute uniformly throughout the parenchyma (Streit, 2001). In healthy brain, microglia display a “resting” phenotype responsible for the continuous immune surveillance of their environment (Fetler and Amigorena, 2005, Raivich, 2005). Studies carried out with GFP-expressing microglia suggest that thorough surveillance of the CNS environment is linked to
Microglial cells express functional cannabinoid receptors
Whether resting microglia found in healthy brain parenchyma express CB1 and/or CB2 receptors has not been addressed directly, but one can presume – as stated at the beginning of this review – that these cells do not express CB2 receptors (because the mRNA encoding for these receptors is undetectable in healthy brain tissue) (Carlisle et al., 2002, Derocq et al., 1995, Galiègue et al., 1995, Griffin et al., 1999, McCoy et al., 1999, Munro et al., 1993, Schatz et al., 1997, Sugiura et al., 2000).
Microglial cells produce and inactivate endocannabinoids
Microglial cells in culture produce anandamide and 2-AG, with ionomycin and millimolar concentrations of ATP selectively increasing 2-AG production (Carrier et al., 2004, Walter et al., 2003). The molecular mechanism underlying ATP-induced 2-AG production involves the activation of P2X7 ionotropic receptors, which are highly permeable to calcium and induce sustained rises in intracellular calcium that directly increase DGL activity while inhibiting MGL activity (Witting et al., 2004a). This
Conclusions
The studies outlined in this review were carried out over the last decade and convincingly show that microglia express many of the components required for functional eCB paracrine and autocrine signaling. Microglia express CB2 receptors and non-psychotropic CB2 agonists regulate their immune-related functions, including migration, proliferation and cytotoxin release. Microglia produce large amounts of eCBs that most likely contribute to the long-lasting increase in eCB levels measured under
Acknowledgments
To the members of my laboratory (Eiron Cudaback, Eric Horne, William Marrs, Aaron Miller, Poulami Mitra, Faith Reyes and Michelle Sexton) for critical reading of this manuscript, and to NIDA (DA 14486, DA21285 and DA22469) for grant support.
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