Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus

@article{Makara2005SelectiveIO,
  title={Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus},
  author={Judit K. Makara and Marco Mor and Darren Fegley and Szil{\'a}rd I. Szab{\'o} and Satish Kathuria and Giuseppe Astarita and Andrea Duranti and Andrea Tontini and Giorgio Tarzia and Silvia Rivara and Tam{\'a}s F. Freund and Daniele Piomelli},
  journal={Nature Neuroscience},
  year={2005},
  volume={8},
  pages={1139-1141}
}
The functions of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid found in the brain, remain largely unknown. Here we show that two previously unknown inhibitors of monoacylglycerol lipase, a presynaptic enzyme that hydrolyzes 2-AG, increase 2-AG levels and enhance retrograde signaling from pyramidal neurons to GABAergic terminals in the hippocampus. These results establish a role for 2-AG in synaptic plasticity and point to monoacylglycerol lipase as a possible drug target. 
View on Springer
escholarship.org
161 Citations
Highly Influential Citations
15
Background Citations
61
Methods Citations
3
Results Citations
3

161 Citations

Citation Type

Citation Type

2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain.
Monoacylglycerol Lipase Limits the Duration of Endocannabinoid-Mediated Depolarization-Induced Suppression of Excitation in Autaptic Hippocampal Neurons
TLDR
Strong pharmacological and anatomical evidence is provided that MGL regulates DSE in autaptic hippocampal neurons and, taken together with other studies, emphasizes that endocannabinoid signaling is terminated in temporally diverse ways.
The antinociceptive effects of intraplantar injections of 2‐arachidonoyl glycerol are mediated by cannabinoid CB2 receptors
2‐arachidonoyl glycerol (2‐AG) is an endogenous cannabinoid with central antinociceptive properties. Its degradation is catalysed by monoacylglycerol lipase (MGL) whose activity is inhibited by…
Endothelium‐dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2‐arachidonoylglycerol
TLDR
The endocannabinoids, N‐arachidonoylethanolamide (anandamide) and 2‐arACHidonoylglycerol (2‐AG) are known to modulate vascular tone, but the extent to which they are inactivated via local metabolism in the vasculature remains unclear.
The inhibition of monoacylglycerol lipase by URB602 showed an anti‐inflammatory and anti‐nociceptive effect in a murine model of acute inflammation
TLDR
The development of MAGL inhibitors could offer an opportunity to investigate the anti‐inflammatory and anti‐nociceptive role of 2‐AG, which have not yet been elucidated.
Endocannabinoids as Modulators of Synaptic Signaling
TLDR
Evidence is summarized that these CB1 receptors are innervated by endogenous cannabinoid ligands (endocannabinoids) that are mobilized from neurons postsynaptic to those terminals expressing the receptors.
Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation*
TLDR
The results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COx-2, which provides a mechanistic basis for opening up new therapeutic approaches forprotecting neurons from inflammation- and excitotoxicity-induced neurodegeneration.
A novel monoacylglycerol lipase inhibitor with analgesic and anti-inflammatory activity.
Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum
TLDR
It is found that stimulation of metabotropic glutamate 5 receptors by 3,5-dihydroxyphenylglycine (DHPG) depressed inhibitory transmission in the striatum through selective involvement of 2-AG metabolism and stimulation of presynaptic CB1 receptors.
The Endocannabinoid 2-Arachidonoylglycerol Is Responsible for the Slow Self-Inhibition in Neocortical Interneurons
TLDR
Since DAGLs produce no endocannabinoid other than 2-AG, these results identify this compound as the autocrine mediator responsible for the postsynaptic slow self-inhibition of neocortical LTS interneurons.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 14 REFERENCES
Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus
TLDR
It is shown that inhibition of cyclooxygenase-2 (COX-2), not fatty acid amide hydrolase (FAAH), prolongs DSI, suggesting that COX- 2 limits endocannabinoid action.
The molecular logic of endocannabinoid signalling
The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made…
Brain monoglyceride lipase participating in endocannabinoid inactivation
TLDR
The results suggest that hydrolysis by means of MGL is a primary mechanism for 2-AG inactivation in intact neurons, and not on the accumulation of anandamide, another endocannabinoid lipid.
Presynaptic Specificity of Endocannabinoid Signaling in the Hippocampus
An endocannabinoid mechanism for stress-induced analgesia
TLDR
The results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia, and identify monoacylglycerol lipase as a previously unrecognized therapeutic target.
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
TLDR
It is shown that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides6–8, and the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats are reported.
Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses
TLDR
The transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons is mediated by retrograde signalling through release of endogenous cannabinoids, indicating that the function of endogenous cannabinoid released by depolarized hippocampal neurons might be to downregulate GABA release.
Role of endogenous cannabinoids in synaptic signaling.
TLDR
The synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation, and the fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release.
Depolarization‐induced retrograde synaptic inhibition in the mouse cerebellar cortex is mediated by 2‐arachidonoylglycerol
TLDR
3 kinds of observations identified 2‐AG as the endocannabinoid involved in depolarization‐induced suppression of inhibition (DSI) in the mouse cerebellum: DSI was abolished by diacylglycerol lipase inhibitors; D SI was potentiated by a monoglyceride lipase inhibitor; andDSI was not changed by an inhibitor of fatty acid amide hydrolase.
Activation of cAMP-dependent protein kinase suppresses the presynaptic cannabinoid inhibition of glutamatergic transmission at corticostriatal synapses.
TLDR
The observation that pretreatment of striatal slices with either KT5720 or another PKA inhibitor, H89, completely abolished the attenuation by forskolin on WIN 55,212-2-induced synaptic depression indicate that the presynaptic inhibitory action of CB(1) receptors at corticostriatal synapses could be negatively regulated by cAMP/PKA-mediated receptor phosphorylation.
...
1
2
...