Cannabinoid receptor type 1

Cannabinoid receptor 1 (brain)
Rendering of CNR1 from PDB 1LVQ
Available structures PDB 1LVQ, 1LVR, 2B0Y, 2KOE
Identifiers
Symbols	CNR1; CANN6; CB-R; CB1; CB1A; CB1K5; CB1R; CNR
External IDs	OMIM: 114610 MGI: 104615 HomoloGene: 7273 IUPHAR: CB1 GeneCards: CNR1 Gene
Gene Ontology Molecular function • receptor activity • cannabinoid receptor activity • protein binding • drug binding Cellular component • microsome • plasma membrane • plasma membrane • integral to plasma membrane Biological process • positive regulation of acute inflammatory response to antigenic stimulus • response to stress • G-protein signaling, coupled to cyclic nucleotide second messenger • G-protein signaling, coupled to cAMP nucleotide second messenger • spermatogenesis • aging • response to nutrient • behavior • memory • positive regulation of neuron projection development • regulation of lipid metabolic process • sensory perception of pain • positive regulation of fever generation • negative regulation of fatty acid beta-oxidation • regulation of synaptic transmission, GABAergic • response to lipopolysaccharide • negative regulation of mast cell activation • negative regulation of dopamine secretion • response to nicotine • response to cocaine • positive regulation of apoptosis • negative regulation of ion transport • response to morphine • response to ethanol • negative regulation of action potential • negative regulation of blood pressure • positive regulation of blood pressure • regulation of insulin secretion • negative regulation of nitric-oxide synthase activity • regulation of synaptic transmission, glutamatergic • maternal process involved in female pregnancy • regulation of feeding behavior • regulation of penile erection Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1268	12801
Ensembl	ENSG00000118432	ENSMUSG00000044288
UniProt	P21554	Q99NU3
RefSeq (mRNA)	NM_001160226.1	NM_007726.3
RefSeq (protein)	NP_001153698.1	NP_031752.1
Location (UCSC)	Chr 6: 88.85 – 88.88 Mb	Chr 4: 34.01 – 34.04 Mb
PubMed search	[1]	[2]

The cannabinoid receptor type 1, often abbreviated to CB₁, is a G protein-coupled cannabinoid receptor located in the brain. It is activated by endocannabinoid neurotransmitters including anandamide and by the compound THC, found in the psychoactive drug cannabis.

Expression

The CB₁ receptor is encoded by the gene or CNR1. Two transcript variants encoding different isoforms have been described for this gene. CNR1 orthologs have been identified in most mammals.

Brain

CB₁ receptors are thought to be the most widely expressed G protein-coupled receptors in the brain. This is key 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. Varying levels of CB₁ expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei and other subcortical regions (e.g. the septal region), cerebellar cortex, and brainstem nuclei (e.g. the periaqueductal gray).

Other

CB₁ is expressed on several cell types of the pituitary gland, in the thyroid gland, and most likely in the adrenal gland. CB₁ is also expressed in several cells relating to metabolism, such as fat cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tract. It is also expressed in the lungs and the kidney.

CB₁ is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua and placenta. It is probably important also for the embryo.

Neuroimaging

The inverse agonist MK-9470 makes it possible to produce in vivo images of the distribution of CB₁ receptors in the human brain with positron emission tomography.

Function

Liver

In the liver, activation of the CB₁ receptor is known to increase de novo lipogenesis, 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.

Gastrointestinal activity

Inhibition of gastrointestinal activity has been observed after administration of Δ⁹-THC, or of anandamide. This effect has been assumed to be CB₁-mediated since the specific CB₁ antagonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB₂-mediated component.

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.

Pain

Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage.^{[citation needed]} This effect is produced by interaction with CB₁ (or CB₁-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitoylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitoylethanolamide, however, does not bind to either CB₁ or CB₂. Its analgesic activity is blocked by the specific CB₂ antagonist SR144528, though not by the specific CB₁ antagonist SR141716A. Hence a CB₂-like receptor was postulated.^{[citation needed]}

Use of antagonists

CB₁ selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). A substantial number of antagonists of the CB1 receptor have been discovered and characterized. TM38837 has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.

Mechanism

Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound. They are activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner.

After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly activated the G protein G_i, which inhibits 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.

Elimination of clinically undesirable psychotropic effects 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) produce most of their effects by binding to both the CB₁ and CB₂ cannabinoid receptors.^{[citation needed]}

The CB₁ receptor can also be modulated allosterically synthetic ligands. in a positive and negative manner. In vivo exposure to Δ9THC impairs long-term potentiation and leads to a reduction of phosphorilated CREB.

Evolution

The CNR1 gene is used in animals as a nuclear DNA phylogenetic marker. This intronless gene has first been used to explore the phylogeny of the major groups of mammals, and contributed to reveal that placental orders are distributed into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires. CNR1 has also proven useful at lower taxonomic levels, e.g., in rodents, and for the identification of dermopterans as the closest primate relatives.

See also

• Discovery and development of Cannabinoid Receptor 1 Antagonists

External links

• "Cannabinoid Receptors: CB₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2205. 

Further reading

• Oddi, S.; Spagnuolo, P.; Bari, M.; Dagostino, A.; MacCarrone, M. (2007). "Differential Modulation of Type 1 and Type 2 Cannabinoid Receptors along the Neuroimmune Axis". International review of neurobiology. International Review of Neurobiology 82: 327–337. doi:10.1016/S0074-7742(07)82017-4. ISBN 9780123739896. PMID 17678969. 
• Gérard, C. M.; Mollereau; Vassart; Parmentier (1991). "Molecular cloning of a human cannabinoid receptor which is also expressed in testis". The Biochemical journal 279 ( Pt 1): 129–134. PMC 1151556. PMID 1718258. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1151556. 
• Hoehe MR, Caenazzo L, Martinez MM, et al. (1991). "Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14-q15". New Biol. 3 (9): 880–5. PMID 1931832. 
• Matsuda LA, Lolait SJ, Brownstein MJ, et al. (1990). "Structure of a cannabinoid receptor and functional expression of the cloned cDNA". Nature 346 (6284): 561–4. Bibcode 1990Natur.346..561M. doi:10.1038/346561a0. PMID 2165569. 
• Gérard C, Mollereau C, Vassart G, Parmentier M (1991). "Nucleotide sequence of a human cannabinoid receptor cDNA". Nucleic Acids Res. 18 (23): 7142. doi:10.1093/nar/18.23.7142. PMC 332788. PMID 2263478. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=332788. 
• Shire D, Carillon C, Kaghad M, et al. (1995). "An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing". J. Biol. Chem. 270 (8): 3726–31. doi:10.1074/jbc.270.8.3726. PMID 7876112. 
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548. 
• Kenney SP, Kekuda R, Prasad PD, et al. (1999). "Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta". Am. J. Obstet. Gynecol. 181 (2): 491–7. doi:10.1016/S0002-9378(99)70583-1. PMID 10454705. 
• Porcella A, Maxia C, Gessa GL, Pani L (2000). "The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein". Eur. J. Neurosci. 12 (3): 1123–7. doi:10.1046/j.1460-9568.2000.01027.x. PMID 10762343. 
• Mukhopadhyay S, Howlett AC (2001). "CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains". Eur. J. Biochem. 268 (3): 499–505. doi:10.1046/j.1432-1327.2001.01810.x. PMID 11168387. 
• Murphy WJ, Eizirik E, Johnson WE, et al. (2001). "Molecular phylogenetics and the origins of placental mammals". Nature 409 (6820): 614–8. doi:10.1038/35054550. PMID 11214319. 
• Nong L, Newton C, Friedman H, Klein TW (2002). "CB1 and CB2 receptor mRNA expression in human peripheral blood mononuclear cells (PBMC) from various donor types". Adv. Exp. Med. Biol.. Advances in Experimental Medicine and Biology 493: 229–33. doi:10.1007/0-306-47611-8_27. ISBN 0-306-46466-7. PMID 11727770. 
• Leroy S, Griffon N, Bourdel MC, et al. (2002). "Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1". Am. J. Med. Genet. 105 (8): 749–52. doi:10.1002/ajmg.10038. PMID 11803524. 
• Schmidt LG, Samochowiec J, Finckh U, et al. (2002). "Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence". Drug and alcohol dependence 65 (3): 221–4. doi:10.1016/S0376-8716(01)00164-8. PMID 11841893. 
• Lastres-Becker I, Cebeira M, de Ceballos ML, et al. (2002). "Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP-treated marmosets". Eur. J. Neurosci. 14 (11): 1827–32. doi:10.1046/j.0953-816x.2001.01812.x. PMID 11860478. 
• Petrelli A, Gilestro GF, Lanzardo S, et al. (2002). "The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met". Nature 416 (6877): 187–90. doi:10.1038/416187a. PMID 11894096. 
• Huang SM, Bisogno T, Trevisani M, et al. (2002). "An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors". Proc. Natl. Acad. Sci. U.S.A. 99 (12): 8400–5. Bibcode 2002PNAS...99.8400H. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=123079. 
• Ujike H, Takaki M, Nakata K, et al. (2002). "CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia". Mol. Psychiatry 7 (5): 515–8. doi:10.1038/sj.mp.4001029. PMID 12082570. 
• Ho BY, Current L, Drewett JG (2002). "Role of intracellular loops of cannabinoid CB(1) receptor in functional interaction with G(alpha16)". FEBS Lett. 522 (1–3): 130–4. doi:10.1016/S0014-5793(02)02917-4. PMID 12095632. 
• Matias I, Pochard P, Orlando P, et al. (2002). "Presence and regulation of the endocannabinoid system in human dendritic cells". Eur. J. Biochem. 269 (15): 3771–8. doi:10.1046/j.1432-1033.2002.03078.x. PMID 12153574. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.