Cannabinoid receptor

The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids.

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Classification

There are currently two known subtypes, CB₁^[1][2] which is expressed mainly in the brain, but also in the lungs, liver and kidneys and CB₂ which is mainly expressed in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptors^[3] 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 a GPCR in the brain was described.^[4]

The protein sequences of CB₁ and CB₂ receptors are about 45% similar. In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. The affinity of an individual cannabinoid to each receptor determines the effect of that cannabinoid. Cannabinoids that bind more selectively to certain receptors are more desirable for medical usage.

CB₁

Main article: Cannabinoid receptor type 1

Cannabinoid receptor type 1 (CB₁) receptors are thought to be the most widely expressed G-protein coupled receptors in the brain. This is due to endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized neuron bind to CB₁ receptors in the pre-synaptic neuron and cause a reduction in GABA release.

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,^[5] Activation of presynaptic CB₁ receptors is also known to inhibit sympathetic innervation of blood vessels and contributes to the suppression of the neurogenic vasopressor response in septic shock.^[6]

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, and are expressed on mouse pre-implantation embryos. It is also expressed on peripheral nerve terminals.In the brain, they are mainly expressed by microglial cells, where their role remains unclear.

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.

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).^[7] 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.^[7]

Cardiovascular activity

Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension. Anandamide and 2-AG, produced by macrophages and platelets respectively, may mediate this effect.

The hypotension in hemorrhaged rats was prevented by the CB₁ antagonist SR 141716A. Recently the same group found that anandamide-induced mesenteric [[va sodilation]] is mediated by an endothelially located SR 141716A-sensitive "anandamide receptor," distinct from the CB₁ cannabinoid receptor, and that activation of such a receptor by an endocannabinoid, possibly anandamide, contributes to endotoxin-induced mesenteric vasodilation in vivo. The highly potent synthetic cannabinoid HU-210, as well as 2-AG, had no mesenteric vasodilator activity. Furthermore it was shown that mesenteric vasodilation by anandamide apparently has 2 components, one mediated by a SR 141716-sensitive non-CB₁ receptor (located on the endothelium) and the other by an SR 141716A-resistant direct action on vascular smooth muscle.

The production of 2-AG is enhanced in normal, but not in endothelium-denuded rat aorta on stimulation with Carbachol, an acetylcholine receptor agonist. 2-AG potently reduces blood pressure in rats and may represent an endothelium-derived hypotensive factor.

Pain

Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage. This effect is produced by interaction with CB₁ (or CB₁-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitylethanolamide, however does not bind to either CB₁ or CB₂. Its analgetic activity is blocked by the specific CB₂ antagonist SR 144528, though not by the specific CB₁ antagonist SR 141716A. Hence a CB₂-like receptor was postulated.

Cannabinoid treatments

Cannabis sativa preparations have been known as therapeutic agents against various diseases for millennia.^[8] The native active constituent, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) was found to be the principal mediator of the effects of cannabis.^[9] Synthetic Δ⁹-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients. U.S. Pat. No. 5,434,295 discloses a family of novel 4-phenyl pinene derivatives, and teaches how to use those compounds in pharmaceutical compositions useful for treating various pathological conditions associated with damage to the central nervous system. U.S. Pat. No. 4,282,248 discloses additional pinene derivatives. These patents do not mention that any of the disclosed compounds are selective for peripheral cannabinoid receptors.

Several synthetic cannabinoids have been shown to bind to the CB₂ receptor with a higher affinity than to the CB₁ receptor. Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB₁/CB₂ binding ratio > 1000. The pharmacology of those known agonists has yet to be described.

Certain tumors, especially gliomas, express CB₂ receptors. Guzman and coworkers have shown that Δ⁹-tetrahydrocannabinol and WIN-55,212-2, two non-selective cannabinoid agonists, induce the regression or eradication of malignant brain tumors in rats and mice.^[10] CB₂ selective agonists are effective in the treatment of pain, various inflammatory diseases in different animal models,^[11]

^[12] osteoporosis^[12] and atherosclerosis.^[13] CB₁ selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB₁ provides neuroprotection after brain injury.^[14]

References

• The Endocannabinoid System Network (ECSN) - CB₁ receptor
• MeSH Cannabinoid+Receptors