Endocannabinoids and cannabinoids interact with endocannabinoid receptors. Endocannabinoids activate receptors on the surface of cells, and this activation works either in feedback loop or to change cell behavior. The Endocannabinoid System (ECS) acts to moderate the functioning of numerous important body aspects, such as homeostasis. Science describes homeostasis as the consistent physiological function.
Research has found two major cannabinoid receptors: CB1 and CB2 (sometimes written as CB1R and CB2R). Research has found many other receptors, but these two are the most studied.
Research finds CB1 receptors throughout the body but are most abundant in the brain and spinal cord neurons. CB2 receptors occur outside of the nervous system on immune system white blood cells and to a lesser extent throughout the body.
The ECS shows an intriguing relation between the brain and the immune system. The brain and nervous system use molecules for communication. The signaling molecules flow from one cell’s membrane to receptors on the membrane of other cells. Parts of the body also signal each other with molecules called hormones. One may argue that the ECS is a hormonal system in that the endocannabinoids circulate with the blood, rather than being secreted into a synapse as with most neurotransmitters.
CB1 Receptor Another curious aspect relates to how similar CB1 and CB2 are to each other. All receptors consist of protein. Cells make proteins according to the genetic code, translating nucleic acid sequences into amino acid strands. Protein strands are made from the body’s 20 amino acids, but the sequence is critical for the protein to fold into a functional form. The folding often takes the form of a helix, a helix being a winding coil.
CB1 and CB2 only have 44% of their amino acids matching in sequence. This matching is called sequence homology. That means that the two sequences originated as a single sequence very far in the past but have undergone extensive mutation since that time. The 44% of matching sequence usually means the conserved matching sequences are critical to the protein’s function. In other words, mutations in the conserved matching sequences results in death (AKA lethal mutation).
The ECS receptors, CB1 and CB2 both contain amino acid sequences that curl into helices. The protein winds back and forth so that the seven helices align next to each other (almost parallel). The sequences between the helices allow bending or hairpin turns, while the helices themselves provide a zone that attracts and sticks to the lipids of the cell membrane. Thus, the receptor is embedded through and across the cell membrane, and contacts both the interior and the exterior of the cell. The exterior binding site attracts the endocannabinoid which, becoming bound, changes the overall shape of the protein. The N-terminus of the receptor protein is on the outside and the interior C-terminal on the inside. The C-terminus cysteine is often combined with a fatty acid, the change being called Palmitoylation. Palmitic acid is a 16-carbon fatty acid and is found in palm oil.
The CB1 receptor (sometimes CB1R) binds and is stimulated by anandamide (AEA) and THC (Tetrahydrocannabinol, the psychoactive component in cannabis). When a drug stimulates a receptor, it is said to be an agonist, so THC and AEA are agonists of CB1R. CBD can block the binding of THC, preventing activation. Thus, CBD may be considered an “antagonist” to CB1R.
Research has repeatedly found that cannabinoids, whether derived from cannabis or made synthetically can have anticancer activity. Cannabinoids can act against common cancers such as breast, prostate, colorectal and lung cancers, among others. The main mechanism of anticancer activity is the induction of apoptosis, triggered by activation of CB1, CB2 and TRPV1 receptors or independently via other pathways.
As an example of another pathway, cannabinoids alter white blood cell infiltration and increase the expression of TIMP-1. The TIMP protein family inhibit metalloproteinases (MMPs), and research suggests this helps apoptosis and reduces cancer cell proliferation.
2-Oleoylglycerol is bound by the receptor GPR119, and activation signals the release of GLP-1. GLP-1 stands for Glucagon-like peptide #1. GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (β-cells) and in the gastrointestinal tract (enteroendocrine cells). Agonists at the GPR119 receptor cause an increase in intracellular cAMP (cyclic adenosine monophosphate). Many different organisms use cAMP for intracellular signaling. GPR119 also has seven helical portions that wind in and out while embedded in the cell membrane
G protein-coupled receptors (GPCRs) can bind a cannabinoid (or another molecule, all such molecules are called ligands). The resulting change in shape (conformation) allows it to act as a Guanine nucleotide Exchange Factor (GEF). The G protein's α subunit dissociates from the β and γ subunits and then acts on intracellular signaling receptors as may be found on the cell’s nuclear membrane. Researchers believe that at least 831 different human genes code for GPCR proteins.
Palmitoyl Ethanolamide (PEA) also affects peroxisomes. Research indicates that PEA is bound by peroxisome proliferator-activated receptor alpha (PPAR-α). PEA also is bound by G-coupled receptors GPR55 and GPR119. These receptors also have the seven helical sections winding in and out of the cell’s lipid membrane. Ligands activate PPARs to become transcription factors to nuclear hormone receptors.
Research has found a class of receptors called Transient Receptor Potential channels (TRP). TRPV1 regulates the influx of calcium cations. Other frequently cited types of TRP include TRPV1-4, TRPM8 and TRPA1. These receptors have lost one loop of the 7 helices. TRPV1 regulates body temperature as well as the sensations of heat and pain. TRPV1 binds the capsaicin from pepper. TRPV1 also plays an important role in triggering immune cells to release inflammatory cytokines, as in the cytokine storm caused by Covid-19 infection. Cannabinoids CBD, CBG, THCV and CBGV all activate TRPV1 (act as agonists).
CBDA, the precursor to CBD binds to 5-HT1A. The 5-HT1A receptor binds serotonin, which is a tryptamine, but CBDA looks nothing like a tryptamine. Tryptamines include serotonin, melatonin, adrenaline, and dopamine, all extremely important molecules regulating metabolism and emotions. Almost all hallucinogens follow a tryptamine format, yet the tiny variations result in huge differences in effect.
Similarly, the molecules identified as activating one receptor may also have effects on other receptors, either activating, blocking, or helping still other molecules to be bound. Receptor proteins may function together and help activate each other. Research has found that use of THC can enable patients to reduce the amount of opioids used. The cannabinoid and opioid receptors become complexed next to each other so when both are stimulated, the effect is greater than if they are not complexed.
Thus, it is highly likely that all of these receptors evolved from an original sequence. Over millennia the genes duplicated repeatedly. After numerous generations, the sequences mutated away from each other as new functions conferred advantages to their owners. The family tree of this evolution will be revealed when scientists sequence these receptors, and those sequences are compared.///