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, ...
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 ag ...
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 ...
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 ''ara ...
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 (lacto ...
. 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 (DAGL) mediate its formation. 2-AG is
synthesized 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 ''ara ...
-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 r ...
(another
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 ...
), 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
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 ...
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 r ...
, was the second
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 ...
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 ...
.
Pharmacology
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 r ...
, formation of 2-AG is calcium-dependent and is mediated by 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 (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 ...
X glioma cells through a CB1 receptor-dependent mechanism.
2-AG is hydrolyzed ''in vitro'' by
monoacylglycerol lipase (MAGL),
fatty acid amide hydrolase (FAAH), and the uncharacterized
serine hydrolase enzymes
ABHD2,
ABHD6 and
ABHD12.
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 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 import ...
s) and
fatty acid binding proteins (FABPs).
Biosynthesis
2-Arachidonoylglycerol is
synthesized 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 ''ara ...
-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 ...
by the action of
diacylglycerol lipase. 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, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
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
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 (als ...
by the action of a
phosphatase
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolase ...
.
See also
*
2-Arachidonoyl glyceryl ether
*
Endocannabinoid transporters
References
Notes
General references
*
{{DEFAULTSORT:Arachidonoylglycerol, 2-
Endocannabinoids
Neurotransmitters
Fatty acid esters
CB1 receptor agonists
Glycine receptor antagonists
Glycerol esters
Arachidonyl compounds