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 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.


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Excerpt from IUPHAR/BPS Guide to Pharmacology
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