Cannabinoid receptor type 1

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Cannabinoid receptor 1 (brain)

Identifiers

Symbols

CNR1; CANN6; CB-R; CB1; CB1A; CB1K5; CNR

External IDs

OMIM: 114610 MGI: 104615 HomoloGene: 7273

Gene ontology
Molecular function:	• receptor activity • cannabinoid receptor activity
Cellular component:	• plasma membrane • integral to plasma membrane
Biological process:	• signal transduction • G-protein signaling, coupled to cyclic nucleotide second messenger • behavior

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

Refseq

NM_016083 (mRNA)
NP_057167 (protein)

NM_007726 (mRNA)
NP_031752 (protein)

Location

Chr 6: 88.91 - 88.93 Mb

Chr 4: 34.25 - 34.28 Mb

Pubmed search

[1]

[2]

The cannabinoid receptor type 1, also known CB₁, is a G protein-coupled cannabinoid receptor that is found in the brain and is activated by the psychoactive drug cannabis and its active compound THC and by a group of endocannabinoid neurotransmitters including anandamide.

1 Expression
2 Function
3 Use of antagonists
4 Mechanism
5 See also
6 References
7 Further reading

[edit] Expression

The CB₁ receptor is encoded by the gene or CNR1.^[1] Two transcript variants encoding different isoforms have been described for this gene.^[1]

[edit] 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).^[2]

[edit] Other

CB₁ is expressed on several cell types of the pituitary gland, in the thyroid gland, and most likely in the adrenal gland.^[2] 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.^[2] 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.^[2]

[edit] 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.^[3]

[edit] Function

[edit] Liver

In the liver, activation of the CB₁ receptor is known to increase de novo lipogenesis,^[4] 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.^[5]

[edit] 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.^[6]

[edit] 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.

[edit] 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.

[edit] Use of antagonists

CB₁ selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB₁ provides neuroprotection after brain injury.^[7]

[edit] 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^[1].

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).^[8] 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^[2]

Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones however, 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]}

[edit] See also

Cannabinoid receptor

[edit] References

^ ^a ^b ^c "Entrez Gene: CNR1 cannabinoid receptor 1 (brain)".
^ ^a ^b ^c ^d ^e Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2006). "The emerging role of the endocannabinoid system in endocrine regulation and energy balance". Endocr. Rev. 27 (1): 73–100. doi:10.1210/er.2005-0009. PMID 16306385.
^ Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ (2007). "[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor". Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9800–5. doi:10.1073/pnas.0703472104. PMID 17535893.
^ Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G (2005). "Endocannabinoid activation at hepatic CB₁ receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". J. Clin. Invest. 115 (5): 1298–305. doi:10.1172/JCI200523057. PMID 15864349.
^ Godlewski G, Malinowska B, Schlicker E (2004). "Presynaptic cannabinoid CB₁ receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats". Br. J. Pharmacol. 142 (4): 701–8. doi:10.1038/sj.bjp.0705839. PMID 15159284.
^ Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA (2004). "Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats". Br. J. Pharmacol. 142 (8): 1247–54. doi:10.1038/sj.bjp.0705889. PMID 15249429.
^ Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001). "An endogenous cannabinoid (2-AG) is neuroprotective after brain injury". Nature 413 (6855): 527–31. doi:10.1038/35097089. PMID 11586361.
^ Demuth DG, Molleman A (2006). "Cannabinoid signalling". Life Sci. 78 (6): 549–63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430.

[edit] Further reading

Oddi S, Spagnuolo P, Bari M, et al. (2007). "Differential modulation of type 1 and type 2 cannabinoid receptors along the neuroimmune axis.". Int. Rev. Neurobiol. 82: 327–37. doi:10.1016/S0074-7742(07)82017-4. PMID 17678969.
Gérard CM, Mollereau C, Vassart G, Parmentier M (1991). "Molecular cloning of a human cannabinoid receptor which is also expressed in testis.". Biochem. J. 279 ( Pt 1): 129–34. PMID 1718258.
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. 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. PMID 2263478.
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. PMID 7876112.
Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery.". Genome Res. 6 (9): 791–806. 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. 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. 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. 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. 493: 229–33. 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. 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. 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. 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. doi:10.1073/pnas.122196999. PMID 12060783.
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. 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. PMID 12153574.

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

v • d • e

Transmembrane receptor: G protein-coupled receptors

Class A: Rhodopsin like

Adrenergic	α1 (A, B, D), α2 (A, B, C), β1, β2, β3

Eicosanoid	CysLT (1, 2), LTB4 (1, 2), FPRL1, OXE, Prostaglandin (DP, EP (1, 2, 3, 4), PGF), Prostacyclin, Thromboxane

Neuropeptide	B/W (1, 2), FF (1, 2), S, Y (1, 2, 4, 5)

Orphan	GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 79, 82, 83, 84, 85, 87, 88, 92, 101, 103, 119, 120, 132, 135, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 172, 173, 174, 176, 177, 182)

Purinergics	Adenosine (A1, A2a, A2b, A3), P2Y, (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)

Serotonin	(all but 5-HT3) 5-HT1 (A, B, D, E, F), 5-HT2 (A, B, C), 5-HT (4, 5A, 6, 7)

Other	Acetylcholine (M1, M2, M3, M4, M5) - Adrenomedullin - Anaphylatoxin (C3a, C5a) - Angiotensin (1, 2) - Apelin - Bile acid - Bombesin (BRS3, GRPR, NMBR) - Bradykinin (B1, B2) - Cannabinoid (CB1, CB2) - Chemokine - Cholecystokinin (A, B) - Dopamine (D1, D2, D3, D4, D5) - EBI2 - Endothelin (A, B) - Estrogen - Formyl peptide (1, L1, L2) - Free fatty acid (1, 2, 3, 4) - FSH - Galanin (1, 2, 3) - Gonadotropin-releasing hormone (1, 2) - Ghrelin - Histamine (H1, H2, H3, H4) - Kisspeptin - Luteinizing hormone/choriogonadotropin - Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) - MAS (1, 1L, D, E, F, G, X1, X2, X3, X4) - Melanocortin (1, 2, 3, 4, 5) - MCHR (1, 2) - Melatonin (1A, 1B)- Motilin - neuromedin (B, U (1, 2)) - Neurotensin (1, 2) - Opioid (Delta, Kappa, Mu, Nociceptin, but not Sigma) - Olfactory - Opsin (3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH) - Orexin (1, 2) - Oxytocin - Oxoglutarate - PAF - Prokineticin (1, 2) - Prolactin-releasing peptide - Protease-activated (1, 2, 3, 4) - Relaxin (1, 2, 3, 4) - Somatostatin (1, 2, 3, 4, 5) - SREB - Succinate - TAAR (1, 2, 3, 5, 6, 8, 9) - Tachykinin (1, 2, 3) - Thyrotropin - Thyrotropin-releasing hormone - Urotensin-II - Vasopressin (1A, 1B, 2)

Class B: Secretin like

Brain-specific angiogenesis inhibitor (1, 2, 3) - Cadherin (1, 2, 3) - Calcitonin - CD97 - Corticotropin-releasing hormone (1, 2) - EMR (1, 2, 3) - Glucagon (GR, GIPR, GLP1R, GLP2R) - Growth hormone releasing hormone - PACAPR1- GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 157) - Latrophilin (1, 2, 3, ELTD1) - Parathyroid hormone (1, 2) - Secretin - Vasoactive intestinal peptide (1, 2)

Class C: Metabotropic
glutamate / pheromone

Calcium-sensing receptor - GABA B (1, 2) - Glutamate receptor (Metabotropic glutamate (1, 2, 3, 4, 5, 6, 7, 8)) - GPRC6A - GPR (156, 158, 179) - RAIG (1, 2, 3, 4) - Taste receptors (TAS1R (1, 2, 3) TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50))

Frizzled / Smoothened

Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) - Smoothened

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