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: cannabinoids (from plants, labs, or produced in the human body) cannabinoid receptors (two kinds, CB1 and CB2) 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…

Anandamide

Up to this point, we haven’t spoken much of the body’s own endocannabinoids. As a quick refresher, the endocannabinoid system consists of receptors and enzymes that metabolize any cannabinoids bonding to those receptors. However, our cannabinoid receptors do not exist for the purpose of consuming externally produced cannabinoids like those found in cannabis. These receptors exist because our bodies produce their own cannabinoids (endocannabinoids), which are used to signal and control various functions. Of all our naturally produced cannabinoids, one of the most important is anandamide (AN). Anandamide, like our other endocannabinoids, is produced on the spot, where needed. It primarily bonds to CB1 receptors, giving it an effect profile similar to THC, the well-known psychoactive ingredient of cannabis. FAAH (fatty acid amide hydrolase) then metabolizes the anandamide, clearing the receptor for re-activation. Because anandamide is produced locally where needed, while external cannabinoids, like THC, are supplied to any tissue, comparing effect differences may be comparing apples to oranges. However, an oversimplification would be that ananadmide is the body’s own THC with a shorter effect endurance. In fact, the name “anadamide” is actually based on the Sanskrit word “ananda”, meaning “joy” or “bliss”. Rimonabant, the failed weight-loss drug we often reference on the blog, blocked CB1 receptors from being activated by anandamide. From known research, we can now safely guess that many of the negative psychological effects of Rimonabant resulted from preventing the body from using its own anandamide. In other words, anandamide seems to hold at least one key…