2-Arachidonoylglycerol

2-Arachidonoylglycerol
IUPAC name

1,3-Dihydroxy-2-propanyl (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenoate
Other names

2-AG, 2-arachidonoylglycerol
Identifiers
CAS number 53847-30-6
PubChem 5282280
ChemSpider 4445451 Y
ChEBI CHEBI:52392 Y
ChEMBL CHEMBL122972 Y
IUPHAR ligand 729
Jmol-3D images Image 1
Properties
Molecular formula C23H38O4
Molar mass 378.3 g/mol
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor.[1][2] It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994-1995, although had been discovered some time before that. The activities of Phospholipase C (PLC) and diacylglycerol lipase (DAGL) meditate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

Contents

Occurrence

2-AG, unlike anandamide (another endocannabinoid), is present at relatively high levels in the central nervous system; it is the most abundant molecular species of monoacylglycerol found in mouse and rat brain (~5-10 nmol/g tissue).[2][3] Detection of 2-AG in brain tissue is complicated by the relative ease of its isomerization to 1-AG during standard lipid extraction conditions. It has been found in maternal bovine and human milk.[4]

Discovery

Shimon Ben-Shabat, of Ben-Gurion University, discovered the chemical.[5] 2-AG was a known chemical compound but its occurrence in mammals and its affinity for the cannabinoid receptors were first described in 1994-1995. A research group at Teikyo University reported the affinity of 2-AG for the cannabinoid receptors in 1994-1995,[6][7] but the isolation of 2-AG in the canine gut was first reported in 1995 by the research group of Raphael Mechoulam at the Hebrew University of Jerusalem, which additionally characterized its pharmacological properties in vivo.[8] 2-Arachidonoylglycerol, next with Anandamide, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system.[9]

Pharmacology

Unlike anandamide, formation of 2-AG is calcium-dependent and is mediated by the activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL).[2] 2-AG acts as a full agonist at the CB1 receptor.[10] At a concentration of 0.3nM, 2-AG induces a rapid, transient increase in intracellular free calcium in NG108-15 neuroblastoma X glioma cells through a CB1 receptor-dependent mechanism.[2] 2-AG is hydrolyzed in vitro by monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and the uncharacterized serine hydrolase enzymes ABHD6 and ABHD12.[11] The exact contribution of each of these enzymes to the termination of 2-AG signaling in vivo is unknown, though it is estimated that MAGL is responsible for ~85% of this activity.[12]

Biosynthesis

2-Arachidonoylglycerol is synthesized from arachidonic acid-containing diacylglycerol (DAG), which is derived from the increase of inositol phospholipid metabolism by the action of diacylglycerol lipase. The molecule can also be formed from pathways like the hydrolysis derived (by diglyceride) from both phosphatidylcholine (PC) and phosphatidic acid (PAs) by the action of DAG lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid by the action of a phosphatase.[13]

See also

References

Notes

  1. ^ Stella N, Schweitzer P, Piomelli D (August 1997). "A second endogenous cannabinoid that modulates long-term potentiation". Nature 388 (6644): 773–8. doi:10.1038/42015. PMID 9285589. 
  2. ^ a b c d Sugiura T, Kodaka T, Nakane S, et al. (January 1999). "Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds". The Journal of biological chemistry 274 (5): 2794–801. doi:10.1074/jbc.274.5.2794. PMID 9915812. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9915812. 
  3. ^ Kondo S, Kondo H, Nakane S, et al. (June 1998). "2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and -independent mechanisms". FEBS letters 429 (2): 152–6. doi:10.1016/S0014-5793(98)00581-X. PMID 9650580. http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(98)00581-X. 
  4. ^ Fride E, Bregman T, Kirkham TC. (April 2005). "Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood.". Experimental Biology and Medicine 230 (4): 225–234. PMID 15792943. http://www.ebmonline.org/cgi/reprint/230/4/225.pdf. 
  5. ^ Pizzorno, Lara; MDiv; MA; LMT. "New Developments in Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam". Longevity Medicine Review. Retrieved 2011-05-26.
  6. ^ Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of Lipids, 36, 71-74 (in Japanese)
  7. ^ Sugiura T, Kondo S, Sukagawa A, et al. (October 1995). "2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain". Biochem. Biophys. Res. Commun. 215 (1): 89–97. doi:10.1006/bbrc.1995.2437. PMID 7575630. http://linkinghub.elsevier.com/retrieve/pii/S0006291X85724370. Retrieved 2009-01-27. 
  8. ^ Mechoulam R, Ben-Shabat S, Hanuš L, et al. (June 1995). "Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors". Biochemical pharmacology 50 (1): 83–90. doi:10.1016/0006-2952(95)00109-D. PMID 7605349. http://linkinghub.elsevier.com/retrieve/pii/000629529500109D. 
  9. ^ Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience Intelligence Unit) (1st ed. ed.). Georgetown, Texas: Springer. pp. 99, 181. ISBN 978-0306482281. 
  10. ^ Savinainen JR, Järvinen T, Laine K, Laitinen JT (October 2001). "Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes". British journal of pharmacology 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC 1572991. PMID 11588122. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1572991. 
  11. ^ Blankman JL, Simon GM, Cravatt BF (December 2007). "A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol". Chemistry & biology 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC 2692834. PMID 18096503. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2692834. 
  12. ^ Savinainen, JR; Saario, SM; Laitinen, JT (2011-03-18). "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors." Acta Physiol. National Center for Biotechnology Information. PubMed.gov.
  13. ^ Köfalvi, Attila (2008). Cannabinoids and the Brain. New York City: Axel Springer AG. p. 15. ISBN 9780387743486. "2-Arachidonoylglycerol can be synthesized from arachidonic acid-containing diacylglycerol derived from increaded inositol phospholid metabolism by the action of a diacylglycerol lipase. 2-Arachidonoylglycerol can also be formed via other pathways such as the hydrolysis of the diaclygly derived from PC and phosphatidic acid by the action of a diacyglycerol lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid by the action of a phosphatase. The relative importance of these pathways may depend on the types of cells and stimuli." 

General references

Amino acids
Endocannabinoids
Gasotransmitters
Monoamines
Purines

Adenosine · ADP · AMP · ATP
Trace amines
Others
See also Template:Neuropeptides

M: PNS

anat(h/r/t/c/b/l/s/a)/phys(r)/devp/prot/nttr/nttm/ntrp

noco/auto/cong/tumr, sysi/epon, injr

proc, drug(N1B)