2-Arachidonoylglycerol (2-AG) is an

endocannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

, an

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the CB₁ receptor and the primary endogenous ligand for the CB2 receptor. It is an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

formed from the

omega-6 fatty acid Omega-6 fatty acids (also referred to as ω-6 fatty acids or ''n''-6 fatty acids) are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the ''n''-6 position, that is, the sixth bond, counting from ...

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...

and

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

. 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 Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates (lactos ...

. The chemical was first described in 1994-1995, although it had been discovered some time before that. The activities of

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

(PLC) and

diacylglycerol lipase Diacylglycerol lipase, also known as DAG lipase, DAGL or DGL, is a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. It catalyzes the hydrolysis of diacylglycerol, releasing a free fatty acid In chemistry, particula ...

(DAGL) mediate its formation. 2-AG is synthesized from

-containing diacylglycerol (DAG).

Occurrence

2-AG, unlike

anandamide Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...

(another

), 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). 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 as well as human milk.

Discovery

2-AG was discovered by

Raphael Mechoulam Raphael Mechoulam ( he, רפאל משולם, bg, Рафаел Мешулам; born 5 November 1930) is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel. Mechoulam is best known for h ...

and his student Shimon Ben-Shabat. 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 is a private university headquartered in the Itabashi ward of Tokyo, Japan. It was established in 1931 as Teikyo Commercial High School (帝京商業高等学校). It became Teikyo University in 1966. It is part of Teikyo Group, a multinational ...

reported the affinity of 2-AG for the cannabinoid receptors in 1994-1995, but the isolation of 2-AG in the canine gut was first reported in 1995 by the research group of

at the

Hebrew University of Jerusalem The Hebrew University of Jerusalem (HUJI; he, הַאוּנִיבֶרְסִיטָה הַעִבְרִית בִּירוּשָׁלַיִם) is a public research university based in Jerusalem, Israel. Co-founded by Albert Einstein and Dr. Chaim Weiz ...

, which additionally characterized its pharmacological properties ''in vivo''. 2-Arachidonoylglycerol, next with

Anandamide Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...

, was the second

discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

Pharmacology

Unlike

, formation of 2-AG is calcium-dependent and is mediated by the activities of

(PLC) and

(DAGL). 2-AG acts as a full agonist at the CB1 receptor. At a concentration of 0.3nM, 2-AG induces a rapid, transient increase in intracellular free calcium in NG108-15

neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...

X glioma cells through a CB1 receptor-dependent mechanism. 2-AG is hydrolyzed ''in vitro'' by

monoacylglycerol lipase Monoacylglycerol lipase (EC 3.1.1.23; systematic name glycerol-ester acylhydrolase, also known as MAG lipase, acylglycerol lipase, MAGL, MGL or MGLL) is an enzyme that, in humans, is encoded by the ''MGLL'' gene. MAGL is a 33-kDa, membrane-associ ...

(MAGL),

fatty acid amide hydrolase Fatty acid amide hydrolase or FAAH (, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene ''FAAH''.; Fun ...

(FAAH), and the uncharacterized

serine hydrolase Serine hydrolases are one of the largest known enzyme classes comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A defining characteristic of these enzymes is the presence of a particular serine at the active site, which ...

enzymes

ABHD2 Abhydrolase domain-containing protein 2 is a serine hydrolase enzyme that is strongly expressed in human spermatozoa. It is a key controller of sperm hyperactivation, which is a necessary step in allowing sperm to fertilize an egg. It is encoded ...

ABHD6 alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene. Function ABHD6 is a serine hydrolyzing enzyme that pos ...

and

ABHD12 alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ''ABHD12'' gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. It is r ...

. 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 in the brain. There have been identified

transport proteins A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

for 2-arachidonoylglycerol and anandamide. These include the

heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...

s (

Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...

s) and fatty acid binding proteins (FABPs).

Biosynthesis

2-Arachidonoylglycerol is synthesized from

-containing diacylglycerol (DAG), which is derived from the increase of inositol phospholipid

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

by the action of

. The molecule can also be formed from pathways like the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

derived (by

diglyceride A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as sur ...

) from both phosphatidylcholine (PC) and phosphatidic acid (PAs) by the action of DAG lipase and the hydrolysis of arachidonic acid-containing

lysophosphatidic acid Lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule. Function LPA acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors called LPAR1, LPAR2, and LPAR3 (also kn ...

by the action of a

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

References

Notes

General references

* {{DEFAULTSORT:Arachidonoylglycerol, 2- Endocannabinoids Neurotransmitters Fatty acid esters CB1 receptor agonists Glycine receptor antagonists Glycerol esters Arachidonyl compounds