2-Arachidonoylglycerol
Encyclopedia
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous
agonist
of the CB1 receptor. 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)
.
(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). 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.
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
at the Hebrew University of Jerusalem
, which additionally characterized its pharmacological properties in vivo. 2-Arachidonoylglycerol, next with Anandamide
, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system
.
, formation of 2-AG is calcium-dependent and is mediated by the activities of phospholipase C
(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
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 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.
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
.
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
of the CB1 receptor. It is an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
formed from the omega-6 fatty acid
Omega-6 fatty acid
n−6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−6 position, that is, the sixth bond, counting from the methyl end.The biological effects of the n−6 fatty acids are largely mediated by their conversion to n-6 eicosanoids...
arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
and glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
. 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
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) and diacylglycerol lipase
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 and monoacylglycerol....
(DAGL) meditate its formation. 2-AG is synthesized
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
from arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
-containing diacylglycerol (DAG)
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
.
Occurrence
2-AG, unlike anandamideAnandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
(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). 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.
Discovery
Shimon Ben-Shabat, of Ben-Gurion University, discovered the chemical. 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 UniversityTeikyo University
is a private university headquartered in the Itabashi ward of Tokyo, Japan. It was established in 1931 as Teikyo Commercial High School by Lee. It became Teikyo University in 1966...
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
Raphael Mechoulam is an Israeli professor of Medicinal Chemistry and Natural Products at the Hebrew University of Jerusalem in Israel...
at the Hebrew University of Jerusalem
Hebrew University of Jerusalem
The Hebrew University of Jerusalem ; ; abbreviated HUJI) is Israel's second-oldest university, after the Technion – Israel Institute of Technology. The Hebrew University has three campuses in Jerusalem and one in Rehovot. The world's largest Jewish studies library is located on its Edmond J...
, which additionally characterized its pharmacological properties in vivo. 2-Arachidonoylglycerol, next with Anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
.
Pharmacology
Unlike anandamideAnandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
, formation of 2-AG is calcium-dependent and is mediated by the activities of phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) and diacylglycerol lipase
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 and monoacylglycerol....
(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
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
X glioma cells through a CB1 receptor-dependent mechanism. 2-AG is hydrolyzed in vitro by monoacylglycerol lipase
Monoacylglycerol lipase
Monoacylglycerol lipase, also known as MAG lipase, MAGL, MGL or MGLL is a protein that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases...
(MAGL), fatty acid amide hydrolase (FAAH), and the uncharacterized serine hydrolase
Serine hydrolase
The serine hydrolase superfamily is one of the largest known enzyme families comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A characteristic defining feature of this superfamily is the presence of an active site nucleophilic serine that is used for the hydrolysis of...
enzymes 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.
Biosynthesis
2-Arachidonoylglycerol is synthesizedBiosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
from arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
-containing diacylglycerol (DAG)
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
, which is derived from the increase of inositol phospholipid
Lipid signaling
Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
by the action of diacylglycerol lipase
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 and monoacylglycerol....
. The molecule can also be formed from pathways like the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
derived (by diglyceride
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
) from both phosphatidylcholine (PC)
Phosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
and phosphatidic acid (PAs) by the action of DAG lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid
Lysophosphatidic acid
Lysophosphatidic acid 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 LPA1, LPA2, and LPA3...
by the action of a phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
.