According to Pertwee (2006), cannabinoids work by binding with cannabinoid receptors found on the cell surfaces throughout the central nervous system (CNS).
Only two cannabinoid receptors have been recognized: the CB1 receptor (cloned in 1990) and the CB2 receptor (cloned in 1993). These two receptors have only 48% amino acid sequence identity, are found in separate tissues, and use different signaling pathways. They are also sensitive to different agonists and antagonists. According to research, cannabinoid receptor activation inhibits adenylate cyclase, which prevents the conversion of ATP to cyclic AMP (cAMP).
An Overview Of Cannabinoid Receptors
CB1 and CB2 receptor protein sequences are roughly 44 percent identical. Only the receptors’ transmembrane regions are considered; the amino acid similarity between the two receptor subtypes is 68 percent. Furthermore, small variants in each receptor have been discovered. Cannabinoids attach to cannabinoid receptors in a reversible and stereo-selective manner. According to research, subtype-selective cannabinoids have been produced, which may benefit treating disorders such as obesity. Cannabinoid receptors are unique to the phylum Chordata. They have a very limited phylogenetic distribution in the animal kingdom. Enzymes in endocannabinoid biosynthesis/inactivation and endocannabinoid signaling (including targets other than CB1/2-type receptors) are found across the animal kingdom. Although cannabinoid receptors are exclusive to Chordates,
In the 1980s, in vitro experiments revealed the presence of cannabinoid receptors in the brain, with the receptor identified as cannabinoid receptor type 1 or CB1. In 1990, the DNA sequence encoding a G-protein-coupled cannabinoid receptor in the human brain was discovered and cloned. These results led to the discovery of a new brain cannabinoid receptor, known as cannabinoid receptor type 2 or CB2 (1993).
CB1 Receptors
According to research, Cannabinoid receptor type 1 (CB1) receptors are assumed to be among the most abundant Gi protein-coupled receptors in the brain. One way they act is endocannabinoid-mediated depolarization-induced suppression of inhibition, a typical type of retrograde signaling in which depolarization of a single neuron causes a decrease in GABA-mediated neurotransmission. Endocannabinoids generated by the depolarized post-synaptic neuron bind to CB1 receptors in the presynaptic neuron, causing a decrease in GABA release due to reduced presynaptic calcium ion entry. [A medical citation is required]. They can be found in other places of the body as well. Activation of the CB1 receptor, for example, is known to enhance de novo lipogenesis in the liver.
CB2 Receptors
According to research, CB2 receptors are found on immune system T cells, macrophages and B cells, hematopoietic cells, and the brain and CNS (2019). They also have a purpose in keratinocytes. They are also found on nerve terminals in the peripheral nervous system. These receptors are involved in antinociception or pain reduction. They are mostly expressed by microglial cells in the brain, where their function is unknown. While immune and immune-derived cells are the most likely cellular targets and executors of CB2 receptor-mediated effects of endocannabinoids or synthetic agonists (e.g., leukocytes, various populations of T and B lymphocytes, mast cells, monocytes/macrophages, microglia in the brain, dendritic cells, astrocytes, etc.), the number of other potential cellular targets is growing.
Other Cannabinoid Receptors
The existence of extra cannabinoid receptors has long been anticipated, owing to the actions of substances like atypical cannabidiol, which exert cannabinoid-like effects on blood pressure and inflammation while not activating CB1 or CB2. The latest research suggests that the N-arachidonoyl glycine (NAGly) receptor GPR18 is the molecular identity of the abnormal cannabidiol receptor and that NAGly, the endogenous lipid metabolite of anandamide (also known as arachidonoylethanolamide or AEA), initiates directed microglial migration in the CNS via GPR18 activation. Other biological research has proposed that the orphan receptor GPR55, based on sequence homology at the binding region, should be classified as a cannabinoid receptor. Additional research revealed that GPR55 did respond.
This profile as a separate non-CB1/CB2 receptor that reacts to a wide range of endogenous and exogenous cannabis ligands led some researchers to believe that GPR55 should be classified as a CB3 receptor. This re-classification may occur in the future. Nevertheless, this is complicated by discovering another putative cannabinoid receptor in the hippocampus. However, its gene is yet to be cloned, implying that there could be two more cannabinoid receptors to be identified to add to the previous ones. GPR119 has been proposed as a fifth cannabinoid receptor. The PPAR family of nuclear hormone receptors can also react to some cannabinoids.
Cannabinoid Therapies
Synthetic tetrahydrocannabinol (THC) is prescribed under the INN dronabinol or the brand name Marinol to treat nausea and appetite stimulation, primarily in people with AIDS and for refractory nausea and vomiting in chemotherapy patients. The use of synthetic THC is becoming increasingly widespread as the acknowledged benefits gain traction in the medical field. THC is also an active element in nabiximols. This cannabis extract was licensed as a botanical medication in the United Kingdom in 2010 as a mouth spray for persons with multiple sclerosis to relieve neuropathic pain, overactive bladder, and other symptoms.
Conclusion
There are two cannabinoid receptor subtypes known as CB1 and CB2. The CB1 receptor is mostly expressed in the brain (central nervous system or “CNS”), although it is also found in the lungs and kidneys. The CB2 receptor is mostly present in the immune system and hematopoietic cells. Still, an additional study has revealed the presence of these receptors in sections of the brain. There is substantial evidence that new cannabinoid receptors, non-CB1, and non-CB2, are expressed in endothelial cells and the CNS. They first identified the interaction of various cannabinoids to the G protein-coupled receptor GPR55 in the brain in 2007.
Reference
Howlett, A. C. (2005). Cannabinoid receptor signaling. Cannabinoids, 53-79.
Pertwee, R. G. (2006). The pharmacology of cannabinoid receptors and their ligands: an overview. International journal of obesity, 30(1), S13-S18.
Howlett, A. C., Blume, L. C., & Dalton, G. D. (2010). CB1 cannabinoid receptors and their associated proteins. Current medicinal chemistry, 17(14), 1382-1393.
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