International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
- A. C. Howlett7,
- F. Barth1,
- T. I. Bonner2,
- G. Cabral4,
- P. Casellas1,
- W. A. Devane5,
- C. C. Felder6,
- M. Herkenham3,
- K. Mackie8,
- B. R. Martin5,
- R. Mechoulam9 and
- R. G. Pertwee10
- 1Sanofi-Synthelabo Recherche, Montpellier, Cedex, France (F.B., P.C.); 2Laboratory of Genetics (T.I.B.) and 3Section on Functional Neuroanatomy (M.H.), National Institute of Mental Health, Bethesda, Maryland; Departments of 4Microbiology and Immunology (G.C.) and5Pharmacology and Toxicology (W.A.D., B.R.M.), Virginia Commonwealth University, Richmond, Virginia; 6Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (C.C.F.); 7Neuroscience of Drug Abuse Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (A.H.); 8Department of Anesthesiology, University of Washington, Seattle, Washington (K.M.); 9Department of Natural Products, Hebrew University, Medical Faculty, El Kerem Campus, Jerusalem, Israel (R.M.); and 10Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom (R.G.P.)
Abstract
Two types of cannabinoid receptor have been discovered so far, CB1 (2.1: CBD:1:CB1:), cloned in 1990, and CB2(2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB1 and CB2 exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB1 receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB1 agonists probably serve as retrograde synaptic messengers. CB2 receptors are present mainly on immune cells. Such cells also express CB1receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
Footnotes
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Address correspondence to: Professor R. G. Pertwee, Co-Chair of the NC-IUPHAR Subcommittee on Cannabinoid Receptors, Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. E-mail: rgp{at}aberdeen.ac.uk
- Abbreviations:
- Δ9-THC
- Δ9-tetrahydrocannabinol
- THC
- tetrahydrocannabinol
- NC-IUPHAR
- International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification
- ACEA
- arachidonyl-2′-chloroethylamide
- ACPA
- arachidonylcyclopropylamide
- anandamide
- arachidonoylethanolamide
- CBD
- cannabidiol
- CCK
- cholecystokinin
- CD40
- cluster of differentiation 40
- CHO
- Chinese hamster ovary
- FAAH
- fatty acid amide hydrolase
- FAK
- focal adhesion kinase
- GABA
- γ-aminobutyric acid
- HU-210
- 6aR,10aR analog of 11-hydroxy-Δ8-THC-dimethylheptyl
- HU-211
- 6aS,10aS analog of 11-hydroxy-Δ8-THC-dimethylheptyl
- IFN-γ
- interferon γ
- IL
- interleukin
- NOS
- nitric-oxide synthase
- iNOS
- inducible NOS
- IP3
- inositol-1,4,5-triphosphate
- MAPK
- mitogen-activated protein kinase
- NMDA
- N-methyl-d-aspartate
- NO
- nitric oxide
- PI3K
- phosphatidylinositol-3-kinase
- PMA
- phorbol 12-myristate 13-acetate
- PMA/Io
- PMA plus calcium ionophore
- R-(+)-WIN55212
- (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanonemesylate (WIN55212-2)
- SAR
- structure-activity relationship
- [35S]GTPγS
- [35S]guanosine-5′-O-(3-thiotriphosphate)
- JWH-051
- 1-deoxy-11-OH-Δ8-THC-dimethylheptyl
- BSA
- bovine serum albumin
- CNS
- central nervous system
- EM
- electron microscope
- AM281
- N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide
- AM251
- N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide
- CP55940
- (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol
- CP55244
- (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexan-1-ol
- AM630
- 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (6-iodopravadoline)
- RT-PCR
- reverse transcription-polymerase chain reaction
- SR141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride
- 5-HT
- 5-hydroxytryptamine
- JNK
- c-Jun N-terminal kinase
- kb
- kilobase(s)
- L-759633
- (6aR,10aR)-3-(1,1-dimethylheptyl)-1-methoxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene
- L-759656
- (6aR,10aR)-3-(1,1-dimethylheptyl)-1-methoxy-6,6-dimethyl-9-methylene-6a,7, 8,9,10,10a-hexahydro-6H-benzo[c]chromene
- JWH-015
- (2-methyl- 1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone
- JWH-133
- 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene
- JWH-139
- 3-(1,1-dimethylpropyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene
- HU-308
- {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3.1.1] hept-2-en-2-yl}-methanol
- CP47497
- 5-(1,1-dimethylheptyl)-2-(3-hydroxy-cyclohexyl)-phenol
- L-768242
- (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone
- WIN54461
- 6-bromo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone
- WIN56098
- anthracen-9-yl-[2-methyl-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-methanone
- U.S. Government
