More cannabinoid receptors other than CB1 and CB2

The way that I understand these cannabinoid receptors is we have classes of receptors that are named after the compounds that activate them (cannabinoids). Cannabinoid receptors are a class of G-Protein Coupled Receptors (GPCR’s) and there have been discoveries of more GPCRS’s that are stimulated by endocannabinoids and phytocannabinoids through years of research. These receptors sit within the cell membrane and upon activation, start a signaling cascade within the cell that leads to specific effects. The most popular cannabinoid receptor is the CB1 receptor. The highest levels of CB1 receptor expressions are in the central nervous system. In fact, there are more CB1 receptors in the brain than any other type of GPCR. It has earned the reputation “brain receptor” but is also found throughout the body in many different tissues: cardiovascular, reproductive, immune, gastrointestinal, and peripheral nerves to name a few important ones. Since CB1 receptors are distributed widely amongst our bodies it is no mistake that it is responsible for these regulations and more.

• Regulates learning and memory
• Neuronal development & synaptic plasticity
• Regulates reward and addiction
• Reduces pain
• Reduces neuroinflammation and degeneration
• Regulates metabolism & food intake
• Regulates bone mass
• Cardiovascular effects

This brings us to the second most commonly known cannabinoid receptor, CB2 receptor. The CB2 receptor is located primarily in the periphery, unlike CB1. It is mainly expressed in immune cells, giving it an important role in inflammation. However, we now know that CB2 is expressed in a variety of cells, including those in the central nervous system, liver, and bone. Thanks to CB2 research, CB1 is no longer considered to be the only cannabinoid receptor that affects memory and cognition.

The amino acid sequence of the CB2 receptor is close to the CB1 receptor. Unsurprisingly, the CB2 receptor is activated by similar endocannabinoids as the CB1 receptor, including anandamide and 2-AG. CB2 receptors support healthy nervous system function, proper immune function, and have soothing and relaxing properties on the body (similar to that of CB1), primarily through their ability to regulate inflammation. However, CB2 activation does not have the same psychoactive side effects as does its counterpart, CB1.

For most articles on the endocannabinoid system and its receptors, the story ends here. But through the late 1990’s and early 2000’s more cannabinoid receptors were identified through research and mice testing. Breeding mice with genetically-deleted CB1 and CB2 receptors were crossbred to create mice that had neither receptor. If no other receptors were supposed to be activated by cannabinoids then it was supposed to stop there. But there were receptors other than CB1 and CB2 that were activated by THC and anandamide in these mice. Starting with the first report in 1999, it was observed that many different effects of cannabinoids, in these double knockout mice, were still present without CB1 and CB2. Examples of effects from cannabinoids were; change in blood pressure, pain, inflammation, and gastric motility with the absence of CB1 and CB2 receptors. Thus, resulting in the discovery that endocannabinoids bind to many receptors that were not considered part of the endocannabinoid system initially.

Introducing G-Protein Coupled Receptors:

GPR18 was discovered in 1997, but for several years it was an “orphan receptor”, meaning that scientists did not know what its ligand was. In 2006, it was discovered that this receptor could be activated by endocannabinoids.
GPR18 can be activated by anandamide, but its main endocannabinoid ligand appears to be N-arachidonyl glycine (NAGly), which is a metabolite of anandamide.
The GPR18 receptor is expressed highly in the spinal cord, small intestine, immune cells, bone, spleen, marrow, thymus, lungs, testis and cerebellum.
GPR18 activation can lower blood pressure. It also has significant functions in immune cells. It acts as a powerful chemoattractant – meaning it induces migration of immune cells.

The next one, GPR55, has a similar story to that of GPR18. It too was an orphan receptor for years until its ligands were discovered. GPR55’s main ligand appears to be another known endocannabinoid called lysophosphatidylinositol (LPI). GPR55 is also activated by 2-AG and anandamide. This receptor is expressed at high levels in the central nervous system, as well as adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder and kidneys. Its wide tissue distribution gives it roles in a variety of body systems.
GPR55 activation causes hypotension (lowers blood pressure), is anti-inflammatory, and is in some cases anti-nociceptive (pain blocking). GPR55 regulates energy intake and expenditure, which could impact diseases such as obesity and diabetes. It is also expressed in bone cells with a possible role in osteoporosis. GPR55 is a neuroprotective and decreased neurodegeneration in models of multiple sclerosis.

Unlike the above receptors, GPR119 expression is restricted to a limited number of tissues. Because it is primarily found in the pancreas and gastrointestinal tract, researchers believe that its role is the regulation of energy and metabolism.
GPR119 has limited activation by endocannabinoids such as 2-AG and anandamide but has been linked to be activated by the endocannabinoid OEA, Oleoylethanolamine.
Activation of GPR119 reduces food intake, improves handling of blood sugar, and decreases body weight. These effects appear to be mediated through regulation of hormones such as insulin and GLP-1.

Transient receptor potential vallinoid (TRPV1):

The next set of receptors are a particular subfamily of the transient receptor potential cation channel. It is of the V family, also know as the vanilloid receptor 1. (TRPV1) is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins, which in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels.
(TRPV1) is an ion channel expressed both in the brain and in sensory nerves. In sensory nerves, TRPV1 acts like a sensor for things that could potentially cause tissue damage. It sends a pain signal to the brain after being activated by heat and proinflammatory substances. The most famous activator of TRPV1 is capsaicin, the ingredient found in chili peppers that causes a burning pain. Chronic pain is also a sign of Dysregulation of TRPV1.

Serotonin Receptors:

Anandamide can directly bind to the 5-HT3 serotonin receptor and activate it. Although it does not work by blocking the main serotonin binding site, it does however, bind to a different site and can act as a negative allosteric modulator. In other words, it changes the structure of the receptor to minimize 5-HT activation.
This process in which anandamide binds to 5-HT3 is at least partly responsible for the analgesic effects of cannabinoids that are not traditionally involving CB1 or CB2 receptors.

Glycine Receptors:
Glycine receptors (GlyRs) are ligand-gated ion channels that are involved in nerve activation. GlyRs are seen to be expressed in spinal interneurons, where they regulate pain transmission to the brain.
In a similar case to anandamide with 5-HT3 receptors, anandamide does not activate GlyRs by itself and does not bind to the main agonist site. But it does however still act as an allosteric modulator, binding to a different site on the GlyR and enhances activation by glycine. This is another mechanism, separate of the CB1 and CB2 receptors, that endocannabinoids may reduce pain by acting at the spinal level.

Peroxisome Proliferator-Activated Receptors:

Peroxisome Proliferator-Activated Receptors or (PPARs) don’t actually sit on the cell membrane like the above mentioned receptors. They in fact reside within the cell and can directly bind to DNA sequences and change transcription of targeted genes. The three isoforms of PPAR are: α, β, and γ.
Although anandamide and 2-AG can potentially activate PPARα, its activation is stronger by endocannabinoids OEA and PEA. Emerging evidence suggests that PPARβ can suppress inflammatory bowel disease through PPARβ -dependent and ligand-independent down-regulation of inflammatory signaling. PPARs regulate cell function throughout the majority of our tissue. Whether it is PPARα or PPARγ activation from endocannabinoids, the list of effects can be neuroprotection against ischemia and neurodegeneration, analgesia, anti-tumor effects, weight loss, vasorelaxation, and anti-inflammation. I will have you know there are already approved drugs that depend on PPARα activation (for treatment of cholesterol disorders and triglyceride metabolism) and PPARγ activation (for treatment of insulin resistance and to decrease blood glucose levels.)

It appears many more mechanisms in our bodies respond to these endocannabinoids and possibly phytocannabinoids. The more we can understand about these receptor sites and how we can contribute to the nourishment of them, I believe we will start to unlock more secrets to healing and the connection between humans and plants. If these receptor sites are activated by the cannabinoids we make internally then there is no telling just how beneficial it could be to feed our bodies all sorts of cannabinoids from external sources. Seems to me these receptors are involved in some big play operations in our bodies and the welfare of those particular systems and receptors could be critical to our body’s overall fight for homeostasis.