What is 2-arachidonoylglycerol?
You may have heard of the endocannabinoid system in our body. But are you familiar with 2-Arachidonoylglycerol or, for short, 2-AG? This endocannabinoid is the most abundant in our body and has a significant role in maintaining the balance of our endocannabinoid system.
They will bind cannabinoid receptors in the central and peripheral nervous system, which are CB1 and CB2. They’re involved in physiological functions, including forms of neuroplasticity or the ability of neural networks to grow and reorganize.
It was first discovered in 1995 and has become the most extensively studied monoacylglycerol.
In this blog post, let’s find out how this substance is synthesized and its importance to our health.
Discovery and Historical Context
The study of the endocannabinoid system was first focused on endogenous cannabinoids and their effects, which then gave way to the exploration of a newly discovered receptor system – the endocannabinoid system.
Cannabinoid receptors were then characterized by Devane et al., who also isolated the first endocannabinoid, arachidonoyl ethanolamide or anandamide. After that, Raphael Mechoulam and his student, Ben-Shabat, discovered the second endocannabinoid known as 2-AG in 1995.
Professor Mechoulam and his team are considered the founders of cannabinoid and endocannabinoid research. Not only were they able to identify 2-AG, but they were also the ones who discovered the structure of plant-derived THC. All these findings make up our current knowledge of how the endocannabinoid system works. 2-AG binds to the CB1 and CB2 receptors, similarly to how THC (tetrahydrocannabinol) and CBD (cannabidiol) bind to these receptors. It will then signal the endocannabinoid system to react accordingly.
While THC and CBD are exogenous and need to be consumed, 2-AG can be synthesized by our body, hence the name endocannabinoid.
Chemical Nature and Synthesis of 2-AG
Chemical Composition
Regarding its chemical composition, 2-AG’s biochemistry is classified as an ester formed from the fatty acid omega-6-arachidonic and glycerol with the molecular formula C23H38O4.
Synthesis Process
There are two main pathways to 2-AG’s biosynthesis: signaling and metabolic pathways. The signaling pathway starts from phosphatidylinositol-4,5-bisphosphate or PIP2, while the metabolic pathway uses arachidonic acid and glycerol.
PIP2 will be converted by phospholipase C, diacylglycerol (DAG), and inositol-1,4,5-triphosphate. The metabolic pathway involves the hydrolysis of triglycerides by hormone-sensitive lipase.
The two pathways will converge and further be processed by diacylglycerol lipase (DAGL) to finally generate 2-AG and a fatty acid.
Comparison with Other Endocannabinoids
There are two major endocannabinoids in our body, which are 2-AG and anandamide. Anandamide was the first to be discovered and thus was more extensively studied. It turns out that 2-AG is more abundant and present in higher concentrations in the brain.
Both bind to cannabinoid receptors, but anandamide acts only as a partial agonist, while 2-AG is a full agonist for CB1 and CB2. A partial agonist means that it triggers a response that is lower than a full agonist.
Another difference is that 2-AG is very selective and binds only to cannabinoid receptors, while anandamide also interacts with others, such as vanilloid receptors.
Lastly, 2-AG is more active in the adult central nervous system as a neuromodulator. At the same time, anandamide is active during development as a growth factor and as a stress-responsive modulator during adult life.
Biological Functions of 2-AG
Physiological Roles
2-AG has been indicated to be a signal mediator that keeps brain homeostasis with its anti-inflammatory and neuroprotective effects when it goes through the hydrolysis process by MAGL. It has also been shown to have a prominent role in regulating anxiety and stress disorders by binding to the CB1 receptors and affecting stress-related hormones.
Moreover, 2-AG is suggested to have a role in maintaining energy balance in humans by regulating ghrelin levels and stimulating satiety.
Impact on Neurotransmitter Release
Another biological function of 2-AG is as a key regulator of neurotransmitter release. 2-AG induces the inhibition of neurotransmitter release by acting retrogradely onto CB1 receptors. This means that 2-AG mediates various forms of long and short-term plasticity.
Degradation and Metabolic Pathways
2-AG degradation involves multiple enzymes, which will decrease 2-AG levels and signaling. The most dominant pathway for 2-AG degradation is through hydrolysis of the ester bond into the arachidonic acid and glycerol.
The enzyme responsible for this degradation is mostly monoacylglycerol lipase (MAGL), but there are also hydrolases (ABHD12 and ABHD6), cyclooxygenase, and lipoxygenase.
Medical Implications and Research
Potential Therapeutic Uses
Based on 2-AG’s biological functions, there are many potential therapeutic uses for the endocannabinoid:
- Seizures: 2-AG suppresses seizures through interaction with the CB1 receptor.
- Neurodegenerative diseases: 2-AG is shown to be neuroprotective and can help with neurodegenerative diseases such as Parkinson’s disease.
- Psychiatric illnesses: 2-AG, along with anandamide, has a role in modulating anxiety and depressive behaviors.
- Appetite suppressants: 2-AG may be used to suppress appetite by regulating ghrelin levels and stimulating satiety.
Research Developments
As the endocannabinoid study is relatively new, you can expect more findings regarding 2-AG, such as its role in suppressing epileptic seizures. Animal studies found that 2-AG suppresses excessive excitability of the object’s neural circuits, thus protecting the brain from seizures.
Another recent finding is its presence in human breast milk. Both 2-AG and anandamide are found in breast milk, with 2-AG levels at much higher levels than anandamide. It was also found that women with higher BMI will have more 2-AG and that there’s a higher concentration during the day.
The Future of 2-AG Research
Since its discovery, we’ve managed to determine the characterization of 2-AG in the endocannabinoid system, how it’s synthesized, and its degradation. Seeing as it has plenty of potential in regulating our brain function, further clinical studies are still needed in terms of understanding its effects on our health and how to best utilize it.
For example, although 2-AG was found in human breast milk, its specific role in infant health remains unidentifiable.
Conclusion
2-AG is the most abundant form of endocannabinoid in our brain that acts as the natural ligand for cannabinoid receptors. It has potential for future medical applications, such as seizures, neurodegenerative diseases, psychiatric illnesses, and appetite suppressants.
Aside from endocannabinoids, another way to balance your endocannabinoid system is through cannabinoids.
2-AG FAQs
How does 2-AG differ from THC and CBD in its effects on the body?
The primary role of 2-AG is to maintain homeostasis or balance in our body, while cannabinoids such as THC and CBD are external sources used for therapeutic properties. 2-AG is produced in “as-needed-basis” naturally, while we can tailor the potency of THC and CBD to produce a certain effect.
What are the potential therapeutic benefits of 2-AG?
2-AG can potentially be beneficial for seizures, as appetite suppressants, to combat neurodegenerative diseases, and to help with psychiatric illnesses.
How is 2-AG involved in regulating bodily functions like pain and stress?
2-AG regulates several bodily functions by binding to the cannabinoid receptors, affecting stress-related hormones and inducing analgesic effects that reduce pain and stress.
What are the challenges in researching and utilizing 2-AG in medicine?
The field of endocannabinoid systems is relatively new, lacks depth, and is involved in an extensive network of bodily functions. It might be difficult to pinpoint its efficacy for certain therapeutic benefits. There are also hundreds of mediators that are chemically related to the endocannabinoids, making it difficult to target.