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Cannabinoid receptor 1 (brain)
Identifiers
Symbols CNR1; CANN6; CB-R; CB1; CB1A; CB1K5; CNR
External IDs OMIM114610 MGI104615 HomoloGene7273 IUPHAR: CB1 GeneCards: CNR1 Gene
RNA expression pattern
PBB GE CNR1 213436 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1268 12801
Ensembl ENSG00000118432 ENSMUSG00000044288
UniProt P21554 Q99NU3
RefSeq (mRNA) NM_016083 NM_007726
RefSeq (protein) NP_057167 NP_031752
Location (UCSC) Chr 6:
88.91 - 88.93 Mb
Chr 4:
34.25 - 34.28 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 the psychoactive drug cannabis, by its active compound THC and by a group of endocannabinoid neurotransmitters including anandamide.

Contents

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] CNR1 orthologs [2] 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).[3]

Other

CB1 is expressed on several cell types of the pituitary gland, in the thyroid gland, and most likely in the adrenal gland.[3] 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.[3] 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.[3]

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.[4]

Function

Liver

In the liver, activation of the CB1 receptor is known to increase de novo lipogenesis,[5] 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.[6]

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.[7]

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. 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 analgesic 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.

Use of antagonists

CB1 selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB1 provides neuroprotection after brain injury.[8]

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 Gi, 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).[9] 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.[3]

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.

A few years ago it was demonstrated with synthetic ligands that the receptor can also be modulated allosterically[10] in a positive[11] and negative[12] manner.

Evolution

The CNR1 gene is used in animals as a nuclear DNA phylogenetic marker.[2] This intronless gene has first been used to explore the phylogeny of the major groups of mammals,[13] 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,[14][15] and for the identification of dermopterans as the closest primate relatives.[16]

See also

References

  1. ^ a b c "Entrez Gene: CNR1 cannabinoid receptor 1 (brain)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1268.  
  2. ^ a b "OrthoMaM phylogenetic marker: CNR1 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000118432_CNR1.xml.  
  3. ^ 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". Endocrine reviews 27 (1): 73–100. doi:10.1210/er.2005-0009. PMID 16306385.   edit
  4. ^ Burns, H.; Van Laere, K.; Sanabria-Bohórquez, S.; Hamill, T.; Bormans, G.; Eng, W.; Gibson, R.; Ryan, C. et al. (2007). "18FMK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor". Proceedings of the National Academy of Sciences of the United States of America 104 (23): 9800–9805. doi:10.1073/pnas.0703472104. PMID 17535893.   edit
  5. ^ Osei-Hyiaman, D.; Depetrillo, M.; Pacher, P.; Liu, J.; Radaeva, S.; Bátkai, S.; Harvey-White, J.; Mackie, K. et al. (2005). "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". The Journal of clinical investigation 115 (5): 1298–1305. doi:10.1172/JCI23057. PMID 15864349.   edit
  6. ^ Godlewski, G.; Malinowska, B.; Schlicker, E. (2004). "Presynaptic cannabinoid CB(1) receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats". British journal of pharmacology 142 (4): 701–708. doi:10.1038/sj.bjp.0705839. PMID 15159284.   edit
  7. ^ Mathison, R.; Ho, W.; Pittman, Q.; Davison, J.; Sharkey, K. (2004). "Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats". British journal of pharmacology 142 (8): 1247–1254. doi:10.1038/sj.bjp.0705889. PMID 15249429.   edit
  8. ^ 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): 527–531. doi:10.1038/35097089. PMID 11586361.   edit
  9. ^ Demuth, D.; Molleman, A. (2006). "Cannabinoid signalling". Life sciences 78 (6): 549–563. doi:10.1016/j.lfs.2005.05.055. PMID 16109430.   edit
  10. ^ Price, M.; Baillie, G.; Thomas, A.; Stevenson, L.; Easson, M.; Goodwin, R.; Mclean, A.; Mcintosh, L. et al. (2005). "Allosteric modulation of the cannabinoid CB1 receptor". Molecular pharmacology 68 (5): 1484–1495. doi:10.1124/mol.105.016162. PMID 16113085.   edit
  11. ^ Navarro, H.; Howard, J.; Pollard, G.; Carroll, F. (2009). "Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter". British journal of pharmacology 156 (7): 1178–1184. doi:10.1111/j.1476-5381.2009.00124.x. PMID 19226282.   edit
  12. ^ Horswill, J.; Bali, U.; Shaaban, S.; Keily, J.; Jeevaratnam, P.; Babbs, A.; Reynet, C.; Wong Kai In, P. (2007). "PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats". British journal of pharmacology 152 (5): 805–814. doi:10.1038/sj.bjp.0707347. PMID 17592509.   edit
  13. ^ Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ (February 2001). "Molecular phylogenetics and the origins of placental mammals". Nature 409 (6820): 614–8. doi:10.1038/35054550. PMID 11214319.  
  14. ^ Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D (2009). "Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades". BMC Evol. Biol. 9: 71. doi:10.1186/1471-2148-9-71. PMID 19341461.  
  15. ^ DeBry RW (October 2003). "Identifying conflicting signal in a multigene analysis reveals a highly resolved tree: the phylogeny of Rodentia (Mammalia)". Syst. Biol. 52 (5): 604–17. doi:10.1080/10635150390235403. PMID 14530129.  
  16. ^ Janecka JE, Miller W, Pringle TH, Wiens F, Zitzmann A, Helgen KM, Springer MS, Murphy WJ (November 2007). "Molecular and genomic data identify the closest living relative of primates". Science 318 (5851): 792–4. doi:10.1126/science.1147555. PMID 17975064.  

External links

Further reading

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








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