GPR55: The Leading Candidate For the CB3 Cannabinoid Receptor

GPR55 is a cell membrane receptor that was first identified in the brain in 1999. It was also cloned that year. By looking at the gene sequence, its physical structure, and the specific molecules that interacted with it, scientists began to speculate that it might be a cannabinoid receptor like CB1 and CB2. The majority of scientists working in this field now seem to feel that GPR55 is indeed a cannabinoid receptor, although there is not yet 100 percent agreement.

In December 2007, a team of Swedish scientists published their findings on GPR55 in the British Journal of Pharmacology. It was entitled, “The orphan receptor GPR55 is a novel cannabinoid receptor.” In that same issue of the British Journal of Pharmacology, a team of researchers from Scotland published their findings. This was entitled, “GPR55: a new member of the cannabinoid receptor clan?” These early papers on GPR55 caused quite a stir among their colleagues and pharmaceutical companies took special notice as well.

It was already known that cannabinoids, like CBD and THC, found in essential oil of the cannabis plant, as well as synthetic versions of these, could be used to target receptors in the endocannabinoid system and treat various diseases. It had also been discovered that the human body creates its own internal cannabinoids, called endocannabinoids, that target these same receptors. Thus, it looked like cannabinoid receptors could be stimulated by both internal endocannabinoids and external cannabinoids. It also looked like synthetic versions of both could be made.

So, if GPR55 really was a third cannabinoid receptor in the endocannabinoid system, learning more about the physiology systems it affects in the body and discovering exactly which cannabinoids could target it specifically could mean a very profitable venture for a pharmaceutical company. So, the research dollars flowed freely! The atmosphere surrounding this effort could be compared to the gold rush days in the Wild West when it was rumored gold had been found in a new place.

Of course, many of us who prefer holistic natural medicine to pharmaceuticals perked up too. Could this GPR55, a potential third cannabinoid receptor, help us understand why CBD oil seems to have so many amazing health benefits? Even if we are not overly thrilled to hear about a pharmaceutical company developing synthetic cannabinoids to patent and sell as a high priced drug, we can learn a lot about how natural cannabinoids interact in the human body by reading the published research funded by these pharmaceutical companies!

Although these papers are highly technical and tedious to wade through, it is fascinating reading because they are revealing many clues about the inner workings of the endocannabinoid system. This elevates our understanding of how the cannabinoids in CBD oil can affect the human body. Further, it begins to unravel the mystery of how all these cannabinoids and receptors are interconnected. This gives us greater insight into why a holistic approach using full spectrum CBD oil containing a variety of cannabinoids might offer distinct advantages over using a single synthetic cannabinoid to treat disease.

Here’s a good example of one of the most fascinating insights to come out the research on GPR55:

It’s looking like specific cannabinoids that target specific endocannabinoid receptors can be easily converted to other specific cannabinoids that target other specific endocannabinoid receptors!! This is a rather astonishing discovery! Let’s examine some of the details of this.

2-AG (2-arachidonyl glycerol) is one of the primary cannabinoids produced inside the human body. Its targets and functions are very similar to CBD in the CBD oil extracted from cannabis.

LPA (lysophosphatidylinositol, more specifically 2-arachidonoyl lysophosphatidylinositol) is the primary cannabinoid produced inside the human body that targets the GPR55 receptor.

LPA is an “agonist” to GPR55, which essentially means LPA signals to the GPR55 receptor to express itself and initiate certain physiological functions. It is not understood fully yet, but when GPR55 receptors and other cannabinoid or cannabinoid-like receptors are stimulated to express themselves, the exact physiological response can vary, perhaps by the exact cells that are stimulated and or perhaps by other messengers that may fine tune or alter that message.

2-AG and its functional relative, CBD, are “antagonists” to GPR55, which essentially means that 2-AG and CBD block GPR55 from expressing itself. We’ll give some examples below where antagonists to GPR55 (and other cannabinoids) could have just as powerful therapeutic potential as agonists to GPR55 (and other cannabinoids).

Now, here’s the key point:

It turns out that an enzyme called monoacylglycerol kinase, can convert 2-AG into LPA and vice versa! This is big news! Scientists call this ability to convert back and forth an “interconversion” so look for this term to become a potential buzzword in the not so distant future. Scientists are also beginning to study other interesting interconversions in the endocannabinoid system too, especially as they study other cell membrane receptors that have a high likelihood of being named endocannabinoid receptors in the future.

This “interconversion” news also begs the question of whether or not the human body is capable of converting the cannabinoids found in full spectrum CBD oil into various other cannabinoids as the need arises? Can certain cannabinoids in full spectrum CBD oil stimulate endocannabinoid receptors inside the body to convert lessor known cannabinoids in the oil into other cannabinoids as needed? It is becoming increasingly apparent that this whole endocannabinoid system is tightly linked together, has a lot of flexibility built in, and can react quickly. It’s not just one cannabinoid working on one receptor in one way… it’s way more flexible and way more complicated than that.

So, where is the research on GPR55, our potential third cannabinoid receptor (CB3) headed?

It looks like antagonists to GPR55, including CBD in CBD oil as well as synthetic cannabinoids being developed by the pharmaceutical industry, could potentially be used to fight some of the most prevalent human diseases.

Stimulating the GPR55 receptors with antagonists has huge potential in fighting a variety of cancers since the GPR55 receptor seems to be involved with stimulating cancerous growth. Many cancers show an elevated level of LPA which some scientists interpret as potentially pointing to an overactive GPR55 receptor as a potential cause of cancer. For those of us who believe in the power of holistic natural medicine, anything we can do to prevent and treat the underlying CAUSE of cancer, rather than just the symptoms as most traditional medicine does, is super exciting. This has the potential to be an actual CURE for cancer and a potential way of decreasing the odds of getting cancer. While an actual cure for cancer or a way to prevent cancer might not be the most profitable product for a pharmaceutical company, it is something truly exciting for those of us interested in natural prevention and cures to think about.

There has already been a great deal of research aimed at using GPR55 antagonists to fight breast cancer, myeloma, ovarian cancer, and colon cancer. According to the American Cancer Society, breast cancer is the second leading cause of cancer death in women. The Centers For Disease Control and Prevention (CDC) reports that 230,815 women (and even 2,109 men!) were diagnosed with breast cancer in the United States in 2013 so finding a cure for breast cancer and a way to prevent breast cancer would be a really big deal. After leukemia and lymphoma, myeloma is the third most common cancer of the blood. It is also considered a cancer of the immune system since it attacks cells that produce natural antibodies in the body. Of course, a diagnosis of ovarian cancer and colon cancer is also devastating news.

Another active area of research involves developing ways to treat osteoporosis with antagonists to GPR55. GPR55 receptors are densely found on osteoclasts. These are the specialized bone cells that continually break down bone required in repairing bone. Breaking down old bone is also required so new bone can be added to keep bones strong. In diseases like osteoporosis, osteoclasts can go into hyperdrive resulting in too much bone loss. So, the idea is that antagonists to the GPR55 receptor may help keep these overactive osteoclasts in check. Keep in mind that CBD is one of the most powerful antagonists to GPR55 to be discovered to date!

GPR55 receptors have also been implemented to be involved in several other important physiological processes including blood vessel vasodilation (important in controlling blood pressure), platelet function, fat cell storage and growth, immune system regulation, modulating insulin release, and vitamin D3 metabolism. The early research on GPR55 portends majorly exciting news over the next decades so stay tuned for more reports on GPR55!