CB1 and CB2 structures.
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system, which is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory.
Cannabinoid receptors are of a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, produced by the mammillary body; plant cannabinoids (such as cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and phytocannabinoids (plant based cannabinoids) are lipophilic, such as fat soluble compounds.
There are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2. The CB1 receptor is expressed mainly in the brain (central nervous system or "CNS"), but also in the lungs, liver and kidneys. The CB2 receptor is expressed mainly in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptors that is, non-CB1 and non-CB2, which are expressed in endothelial cells and in the CNS. In 2007, the binding of several cannabinoids to the G protein-coupled receptor GPR55 in the brain was described.
The protein sequences of CB1 and CB2 receptors are about 44% similar.
When only the transmembrane regions of the receptors are considered,
amino acid similarity between the two receptor subtypes is approximately
68%. In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively
to the cannabinoid receptors. Subtype selective cannabinoids have been
developed which theoretically may have advantages for treatment of
certain diseases such as obesity.
It appears that cannabinoid receptors are unique to the phylum Chordata and, as such, they have a rather restricted phylogenetic distribution in the animal kingdom. However, enzymes involved in biosynthesis/inactivation of endocannabinoids
and endocannabinoid signalling in general (involving targets other than
CB1/2-type receptors) occur throughout the animal kingdom. Although the cannabinoid receptors are unique to Chordates, other
organisms are still able to process the endocannabinoids through other
techniques.
CB1
Cannabinoid receptor type 1 (CB1) receptors are thought to be one of the most widely expressed Gαi protein-coupled receptors in the brain. One mechanism through which they function is endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of retrograde signaling, in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized post-synaptic neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release due to limited presynaptic calcium ions entry.
They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis.
Prenatal cannabis exposure (PCE) perturbs the fetal endogenous cannabinoid signaling system (ECSS) which affects neurodevelopment and results in abnormalities in cognition and neuropsychiatric disorders.
CB2
CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes. They are also expressed on peripheral nerve terminals. These receptors play a role in antinociception, or the relief of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear. While the most likely cellular targets and executors of the CB2
receptor-mediated effects of endocannabinoids or synthetic agonists are
the immune and immune-derived cells (e.g. leukocytes, various
populations of T and B lymphocytes, monocytes/macrophages, dendritic
cells, mast cells, microglia in the brain, Kupffer cells in the liver,
astrocytes, etc.), the number of other potential cellular targets is
expanding, now including endothelial and smooth muscle cells,
fibroblasts of various origins, cardiomyocytes, and certain neuronal
elements of the peripheral or central nervous systems.
Other cannabinoid receptors
The existence of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as abnormal cannabidiol that produce cannabinoid-like effects on blood pressure and inflammation, yet do not activate either CB1 or CB2.[18][19] Recent research strongly supports the hypothesis that the N-arachidonoyl glycine (NAGly) receptor GPR18
is the molecular identity of the abnormal cannabidiol receptor and
additionally suggests that NAGly, the endogenous lipid metabolite of anandamide (also known as arachidonoylethanolamide or AEA), initiates directed microglial migration in the CNS through activation of GPR18. Other molecular biology studies have suggested that the orphan receptor GPR55
should in fact be characterised as a cannabinoid receptor, on the basis
of sequence homology at the binding site. Subsequent studies showed
that GPR55 does indeed respond to cannabinoid ligands. This profile as a distinct non-CB1/CB2
receptor that responds to a variety of both endogenous and exogenous
cannabinoid ligands, has led some groups to suggest GPR55 should be
categorized as the CB3 receptor, and this re-classification may follow in time. However this is complicated by the fact that another possible cannabinoid receptor has been discovered in the hippocampus, although its gene has not yet been cloned,
suggesting that there may be at least two more cannabinoid receptors to
be discovered, in addition to the two that are already known. GPR119 has been suggested as a fifth possible cannabinoid receptor, while the PPAR family of nuclear hormone receptors can also respond to certain types of cannabinoid.
Signaling
Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.
Similar responses are produced when introduced in alternative methods,
only in a more concentrated form than what is naturally occurring.
After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK). However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.
Separation between the therapeutically undesirable psychotropic
effects, and the clinically desirable ones, however, has not been
reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors —anandamide and 2-arachidonylglycerol (2-AG)— produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. While the effects mediated by CB1, mostly in the central nervous system, have been thoroughly investigated, those mediated by CB2 are not equally well defined.
Cannabinoid treatments
Synthetic tetrahydrocannabinol (THC) is prescribed under the INN dronabinol or the brand name Marinol, to treat vomiting and for enhancement of appetite, mainly in people with AIDS as well as for refractory nausea and vomiting in people undergoing chemotherapy.
Use of synthetic THC is becoming more common as the known benefits
become more prominent within the medical industry. THC is also an active ingredient in nabiximols, a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.
