Human CNR1

Cannabinoid receptors

Cannabinoid receptors are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of... [read more] differential susceptibility of endogenous ligands to enzymatic conversion [1].

There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB₁ and CB₂ receptors [2]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB₁/CB₂ receptor agonist, and synthetic Δ⁹-tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly Δ⁹-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.

The cannabinoid receptor family is denoted by the abbreviation 'CB' and receptors are numbered by their order of discovery, denoted by a numerical subscript (e.g. CB₁, CB₂). Two cannabinoid receptors have been described to date.

The CB₁ cannabinoid receptor has been cloned from rat [3], mouse [4] and human [5] tissues (97-99% amino acid (aa) sequence identity across species). Its structure is that of a seven-transmembrane domain (7TM) receptor [3] consistent with biochemical and cellular determinations of signal transduction via G proteins [6,7,8,9,10,11]. The CB₁ receptor mRNA and protein are found primarily in brain and nervous tissue [3,12,13,14].

The CB₂ cannabinoid receptor was discovered in a human leukemia HL60 library as a cDNA fragment that exhibited 68% homology with the CB₁ cannabinoid receptor, and mRNA is found primarily in immune tissue [15]. Expressed CB₂ receptor protein was shown to bind cannabinoid and aminoalkylindole compounds and to signal a response through the inhibition of adenylate cyclase [15,16,17,18,19]. The mouse [20] and rat [21] CB₂ receptors have been cloned and exhibit 82% and 81% sequence identity, respectively to the human CB₂ receptor.

Cannabinoid CB₁ and CB₂ receptors are phylogenetically restricted to the chordate branch of the animal kingdom [22]. Among other established G protein-coupled receptors (GPCRs), those most closely related to CB₁/CB₂-type receptors are the lysophospholipid receptors S1P₁, S1P₂, S1P₃, S1P₄, S1P₅, LPA₁, LPA₂ and LPA₃. These receptors for endocannabinoids or lysophospholipid-like molecules have evolved independently in different branches of the GPCR superfamily but CB₁ and CB₂ are the only bona fide ‘cannabinoid receptors’ that have been identified to-date.

References

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2. Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond, B, Biol Sci 2012;367:3353-63.
3. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-4.
4. Chakrabarti A, Onaivi ES, Chaudhuri G. Cloning and sequencing of a cDNA encoding the mouse brain-type cannabinoid receptor protein. DNA Seq 1995;5:385-8.
5. Gérard C, Mollereau C, Vassart G, et al. Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res 1990;18:7142.
6. Pacheco M, Childers SR, Arnold R, et al. Aminoalkylindoles: actions on specific G-protein-linked receptors. J Pharmacol Exp Ther 1991;257:170-83.
7. Howlett AC, Qualy JM, Khachatrian LL. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 1986;29:307-13.
8. Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA 1992;89:3825-9.
9. Sim LJ, Selley DE, Childers SR. In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate binding. Proc Natl Acad Sci USA 1995;92:7242-6.
10. Selley DE, Stark S, Childers SR. Cannabinoid receptor stimulation of [³⁵S]GTPγS binding in rat brain membranes. Life Sci 1996;59:659-668.
11. Childers SR, Deadwyler SA. Role of cyclic AMP in the actions of cannabinoid receptors. Biochem Pharmacol 1996;52:819-27.
12. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990;87:1932-6.
13. Jansen EM, Haycock DA, Ward SJ, et al. Distribution of cannabinoid receptors in rat brain determined with aminoalkylindoles. Brain Res 1992;575:93-102.
14. Mailleux P, Parmentier M, Vanderhaeghen JJ. Distribution of cannabinoid receptor messenger RNA in the human brain: an in situ hybridization histochemistry with oligonucleotides. Neurosci Lett 1992;143:200-4.
15. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-5.
16. Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 1995;48:443-50.
17. Slipetz DM, O'Neill GP, Favreau L, et al. Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. Mol Pharmacol 1995;48:352-61.
18. Showalter VM, Compton DR, Martin BR, et al. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther 1996;278:989-99.
19. Bouaboula M, Poinot-Chazel C, Marchand J, et al. Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur J Biochem 1996;237:704-11.
20. Shire D, Calandra B, Rinaldi-Carmona M, et al. Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. Biochim Biophys Acta 1996;1307:132-6.
21. Griffin G, Tao Q, Abood ME. Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor. J Pharmacol Exp Ther 2000;292:886-94.
22. Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev 2010;62:588-631.

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