2x Emerald Cup Winner – Voted Best Dispensary in Los Angeles and SoCal in 2023 and 2022

The Hunt to Establish New Cannabinoid Receptors: G Protein Pathways

For readers of the blog, we’ve always broken the endocannabinoid system down as follows:

  1. cannabinoids (from plants, labs, or produced in the human body)
  2. cannabinoid receptors (two kinds, CB1 and CB2)
  3. enzymes that break down cannabinoids

Readers will therefore be surprised to learn that beyond CB1 and CB2, there are likely two other receptors in the human body that are capable of receiving cannabinoids. The scientific community is now informally calling these CB3 and CB4, although since these receptors are active in multiple signaling systems, the naming seems irrelevant. Today, we will focus on the receptor known as “GPR55”.

“GPR” and “GPCR” stand for “G protein receptor” and “G protein-coupled receptor” respectively. Both terms mean receptors that are bonding sites for G proteins. G protein receptors are the largest family of signal transducers, with roughly 1000 kinds. These receive hormones, neurotransmitters, odors, light-sensitive compounds, etc. and can be located all throughout the brain and body. In fact, GPCR-creating DNA accounts for almost 3% of our human genome! Readers may not be surprised that GPCRs, with all these applications, therefore account for the target sites of 40-60% of modern pharmaceuticals.

However, not all GPCRs are characterized. Researchers have identified around 150 GPCRs with unknown ligands (signaling molecules). Finding a signaling molecule for a new receptor might be akin to finding a needle in a haystack. Imagine sitting in front of a padlock with thousands and thousands of keys and painstakingly trying each one. For this reason, these receptors are referred to as “orphan GPCRs”. One such orphan GPCR was GPR55, which is expressed in the lungs, liver, bladder, kidney, adrenal glands, and other areas of the body. In the early 2000s, a computer simulation identified GPR55 as a potential cannabinoid target, which spurred cannabinoid research on the receptor. Researchers found that THC activates the receptor, as well as 2AG, one of the body’s own naturally-produced cannabinoids, along with countless other cannabinoids. However, two issues existed with this research. First, quite a few cannabinoids had no effect at all on the receptor. Second, researchers disagreed on the mechanism of action of the cannabinoids that did signal the receptor.

The breakthrough here was the discovery that lysophosphatidylinositol (LPI) compounds are actually the major group of endogenous compounds to activate GPR55. These lipid compounds do not resemble cannabinoids although their activation of GPR55 receptors technically classifies them as endocannabinoid neurotransmitters. Scientists speculate heavily that LPI plays a role in the spread of cancer. In fact, numerous studies have found heavy activation of GPR55 to be “pro-carcinogenic”. This quality forms the basis of cancer research on the receptor. However, based on the expression pattern of GPR55 in the brain, it is also speculated to be involved in re-absorption of bone as well as energy intake/expenditure.

In the formation of bone, agonists of GPR55, which activate it, tend to discourage osteoclast growth. Osteoclasts are bone cells that secrete minute amounts of acid and collagenase to dissolve the hard, mineral bone structure itself. While that sounds brutal, it happens all the time without you noticing, and it allows bones to restructure, repair, and adapt. Increasing osteoclast activity generally means absorbing more bone, while decreasing activity allows bone cell growth. Researchers speculate that GPR55 is involved in bone cell regulation and thus further research may hold the key to solving bone-degenerative diseases, such as osteoporosis. However, the story here is not so simple as “increase GPR55 activation, increase bone mass”, because although GPR55 activation decreases osteoclast growth, it also increases their ability to absorb bone. As with so many systems in the human body, changing one factor changes several others at the same time. As a result, more research will have to be done to determine if GPR55 activation could be a potential treatment for maladaptive bone conditions.

In regard to energy management, several links have been made to GPR55. First, LPI, the main endogenous ligand or signaling molecule, is involved in the stimulation of the release of insulin. Insulin is involved in overall body metabolism, since it helps control what free energy is available in the blood. In support of this, LPI blood plasma levels were found to be higher in obese patients than healthy weight patients. However, GPR55 may also be involved in the neurological signaling that controls energy usage. Supporting this theory, researchers noticed that receptor expression increased after periods of fasting, indicating that the receptor might trigger an adaptive response that conserves energy when food is not available.

Coming full circle, whether these receptors are classified as predominantly cannabinoid receptors or LPI receptors is somewhat irrelevant and arbitrary. The fact remains that these receptors are activated by many cannabinoids and affect multiple systems throughout the human body. Studying these receptors by triggering them with both cannabinoids and non-cannabinoids, therefore, will continue to be an area in which cannabis-related science is contributing to new medicines and cures.


Works Cited

Derek Shore and Patricia Reggio. “The therapeutic potential of orphan GPRCs, GPR35 and GPR55.” (2015) Frontiers in Pharmacology 6:69.