GPR55: The Third Cannabinoid Receptor?

The cannabis plant is home to a family of compounds known as cannabinoids. There is estimated to be over 100 cannabinoids produced by the plant, including the highly controversial yet medicinal (and psychoactive) THC. Many of these cannabinoids have barely been touched on by science, however, research on cannabinoids THC and CBD is constantly expanding. Already, many of the biological mechanisms of these compounds have been uncovered.

Cannabinoids assert their unique effects within the human body in numerous ways. One of which is via interfacing with multiple receptor sights that make up what is known as the endocannabinoid system (ECS).

This system is known to be made up of two primary cannabinoid receptors, CB1 and CB2. THC is known to activate the CB1 receptor site, whereas CBD is known to affect these receptor sites in an indirect fashion. CB1 receptors are found in the brain, spinal nerves, and peripheral nerves. CB2 receptors are largely found throughout the immune system, especially within the spleen.

What makes cannabinoids activate these receptors is their molecular similarity with molecules produced within the body, known as endocannabinoids. For example, THC is very structurally similar to the endocannabinoid anandamide, which is even known to induce altered states of consciousness, such as the “runner’s high”.

But cannabinoids’ effects span further afield than just the CB1 and CB2 receptors; a recently discovered receptor named the GPR55 receptor may play an important role in how cannabinoids affect the body. The site is now even being called the “third cannabinoid receptor”.

GPR55: A POTENTIAL THIRD CANNABINOID RECEPTOR?

The endocannabinoid system was first discovered in the 1940s, and its basic structure and function was understood by the 1960s. GPR55, a G protein-coupled receptor, was not discovered until 1999.

Since that time, it has been found that this site is activated by numerous cannabinoids including THC, the anandamide analogue methanandamide, and JWH015, establishing GPR55 as a cannabinoid receptor distinctly different from CB1 and CB2 sites. GPR55 has been found to be 13% identical to the CB1 receptor and 14.4% identical to the CB2 receptor, and is present within the brain and the peripheral nervous system.

IS GPR55 THE KEY TO CBD EFFECTIVENESS?

CBD has gained immense popularity and recognition over the the last few years as a non-psychoactive cannabinoid that displays vast medicinal potential. Research has delved into the antitumour, anticonvulsant, and anti-inflammatory effects of the compound, with very promising results. CBD has shown little affinity for CB1 and CB2 receptors, and is said to achieve its mechanism primarily via other means. The cannabinoid has been shown to be drawn towards vanilloid receptors and the 5-HT1A receptor.

Whereas other cannabinoids have been shown to bind to the GPR55 receptor, CBD may actually block the receptor’s activity, and this may be how it achieves some of its medicinal benefits.

For example, early in vitro research^[1] has shown that GPR55 may play a role in cancer. GPR55 expression correlates with the invasive potential of metastatic cells and bone metastasis formation of different types of tumours. GPR55 signalling may play a role in cancer progression, such as in lymphoproliferative diseases.

On the other hand, the reduction and blocking of GPR55 activity, as induced by CBD, has been shown to exhibit anti-tumour effects in certain types of cancer including colorectal, breast, pancreatic, and brain.

CBD, GPR55, AND EPILEPSY

Parts of CBD’s rise to mass recognition is its apparent effectiveness against seizures in both clinical trials and anecdotal reports. However, the mechanism of action still remains somewhat a mystery, although CBD’s interaction with the GPR55 receptor may play a crucial role.

In cases of Dravet syndrome, a rare form of epilepsy featuring seizures that are often triggered by hot temperatures or fever, CBD has been shown^[2] to have an ameliorative effect on seizure frequency, duration, and severity when tested in mouse models. The therapeutic effects of CBD here may be mediated by blocking GPR55 receptor activity within the hippocampus, an area of the brain associated with long-term memory and spatial navigation.

INFLAMMATORY BOWEL DISEASE

Many people experiencing Crohn's disease speak of relief when they consume cannabis, and this could be in part due to CBD’s inhibition of GPR55 activity. Crohn's disease falls under the umbrella of irritable bowel syndrome, a condition characterised by abdominal pain, excess gas, diarrhea and constipation, and mucus in the stool. The condition can be triggered by a variety of factors such as food, stress, and hormones.

Irritable bowel syndrome is in part caused by inflammation within the intestines. Interestingly, the blocking of GPR55 shows a reduction in intestinal inflammation within mouse models. With CBD shown to block this receptor, it may display promise in the future treatment of these conditions.