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CNR1  -  cannabinoid receptor 1 (brain)

Homo sapiens

Synonyms: CANN6, CB-R, CB1, CB1A, CB1K5, ...
 
 
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Disease relevance of CNR1

 

Psychiatry related information on CNR1

 

High impact information on CNR1

  • Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors [11].
  • Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain [11].
  • Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-beta1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts [2].
  • Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis [2].
  • These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade [12].
 

Chemical compound and disease context of CNR1

 

Biological context of CNR1

  • We found a significant association of single polymorphisms (P = 0.0014) and haplotypes (P = 0.0001) encompassing the CNR2 gene on human chromosome 1p36, whereas we found no convincing association for CNR1 [18].
  • The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type [8].
  • Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028) [8].
  • The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor [19].
  • Endocannabinoids and cannabinoid receptor genetics [20].
 

Anatomical context of CNR1

  • Cannabinoid receptor type 1 (CB1) is widely distributed in neurons and nonneuronal cells in brain and peripheral organs including sperm, eggs, and preimplantation embryos [21].
  • The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum [19].
  • Despite this similarity in binding epitopes, CB1 variants antagonize BAFF-dependent human B-cell proliferation in vitro and are effective at reducing murine B-cell populations in vivo, showing significant promise as therapeutics for human B-cell-mediated diseases [22].
  • In addition, polymerase chain reaction amplification of the CB1 coding region in the IM-9 cell line cDNA resulted in two fragments, one containing the whole CB1 coding region and the second lacking a 167-base pair intron within the sequence encoding the amino-terminal tail of the receptor [23].
  • In addition, electron microscopy experiments revealed that CB1 and OX1R are closely apposed at the plasma membrane level; they are close enough to form hetero-oligomers [4].
 

Associations of CNR1 with chemical compounds

  • In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003) [1].
  • Adverse effects of elevated levels of anandamide on these processes resulting from FAAH inactivation are mimicked by administration of (-)-Delta9-tetrahydrocannabinol (THC; the major psychoactive constituent of marijuana), due to enhanced signaling via CB1 [21].
  • The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase [19].
  • This alternatively spliced form would translate to an NH2-terminal modified isoform (CB1A) of the receptor, shorter than CB1 by 61 amino acids [23].
  • The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) bind to G protein-coupled central and peripheral cannabinoid receptors CB1 and CB2, respectively [24].
  • Induction of expression of the modified cannabinoid CB1 receptor did not limit DAMGO-mediated ERK1/2 MAP kinase phosphorylation and did not allow SR141716A to enhance the function of DAMGO [25].
 

Physical interactions of CNR1

  • The observation that the phenolic hydroxyl of THCs was important for binding to the CB1 receptor but not as critical for binding to the CB2 receptor prompted us to extend this finding to the cannabinol (CBN) series [26].
  • Two recently published patents indicate that several cannabinoid receptor ligands also bind to the orphan G-protein-coupled receptor GPR55 [27].
 

Enzymatic interactions of CNR1

  • The characterization, cloning, and neuronal distribution of FAAH have been detailed and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide which serves as the endogenous ligand for the cannabinoid receptor [28].
  • Treatment with SB-674042 also reduced the potency of a CB1 receptor agonist to phosphorylate ERK1/2 only when the two receptors were co-expressed [29].
 

Regulatory relationships of CNR1

 

Other interactions of CNR1

 

Analytical, diagnostic and therapeutic context of CNR1

References

  1. Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1). Barrero, F.J., Ampuero, I., Morales, B., Vives, F., de Dios Luna Del Castillo, J., Hoenicka, J., García Yébenes, J. Pharmacogenomics J. (2005) [Pubmed]
  2. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Teixeira-Clerc, F., Julien, B., Grenard, P., Tran Van Nhieu, J., Deveaux, V., Li, L., Serriere-Lanneau, V., Ledent, C., Mallat, A., Lotersztajn, S. Nat. Med. (2006) [Pubmed]
  3. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Sarfaraz, S., Afaq, F., Adhami, V.M., Mukhtar, H. Cancer Res. (2005) [Pubmed]
  4. Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. Hilairet, S., Bouaboula, M., Carrière, D., Le Fur, G., Casellas, P. J. Biol. Chem. (2003) [Pubmed]
  5. Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Carriba, P., Ortiz, O., Patkar, K., Justinova, Z., Stroik, J., Themann, A., Müller, C., Woods, A.S., Hope, B.T., Ciruela, F., Casadó, V., Canela, E.I., Lluis, C., Goldberg, S.R., Moratalla, R., Franco, R., Ferré, S. Neuropsychopharmacology (2007) [Pubmed]
  6. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Schmidt, L.G., Samochowiec, J., Finckh, U., Fiszer-Piosik, E., Horodnicki, J., Wendel, B., Rommelspacher, H., Hoehe, M.R. Drug and alcohol dependence. (2002) [Pubmed]
  7. Human cannabinoid receptor 1: 5' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Zhang, P.W., Ishiguro, H., Ohtsuki, T., Hess, J., Carillo, F., Walther, D., Onaivi, E.S., Arinami, T., Uhl, G.R. Mol. Psychiatry (2004) [Pubmed]
  8. CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Ujike, H., Takaki, M., Nakata, K., Tanaka, Y., Takeda, T., Kodama, M., Fujiwara, Y., Sakai, A., Kuroda, S. Mol. Psychiatry (2002) [Pubmed]
  9. Altered cannabinoid receptor mRNA expression in peripheral blood mononuclear cells from marijuana smokers. Nong, L., Newton, C., Cheng, Q., Friedman, H., Roth, M.D., Klein, T.W. J. Neuroimmunol. (2002) [Pubmed]
  10. Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Leroy, S., Griffon, N., Bourdel, M.C., Olié, J.P., Poirier, M.F., Krebs, M.O. Am. J. Med. Genet. (2001) [Pubmed]
  11. Role of endogenous cannabinoids in synaptic signaling. Freund, T.F., Katona, I., Piomelli, D. Physiol. Rev. (2003) [Pubmed]
  12. Modulation of anxiety through blockade of anandamide hydrolysis. Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., La Rana, G., Calignano, A., Giustino, A., Tattoli, M., Palmery, M., Cuomo, V., Piomelli, D. Nat. Med. (2003) [Pubmed]
  13. Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells. Sarnataro, D., Grimaldi, C., Pisanti, S., Gazzerro, P., Laezza, C., Zurzolo, C., Bifulco, M. FEBS Lett. (2005) [Pubmed]
  14. CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. Mukhopadhyay, S., Howlett, A.C. Eur. J. Biochem. (2001) [Pubmed]
  15. Association study of the CNR1 gene exon 3 alternative promoter region polymorphisms and substance dependence. Herman, A.I., Kranzler, H.R., Cubells, J.F., Gelernter, J., Covault, J. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2006) [Pubmed]
  16. G protein-coupled endothelial receptor for atypical cannabinoid ligands modulates a Ca2+-dependent K+ current. Begg, M., Mo, F.M., Offertaler, L., Bátkai, S., Pacher, P., Razdan, R.K., Lovinger, D.M., Kunos, G. J. Biol. Chem. (2003) [Pubmed]
  17. 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces the migration of EoL-1 human eosinophilic leukemia cells and human peripheral blood eosinophils. Oka, S., Ikeda, S., Kishimoto, S., Gokoh, M., Yanagimoto, S., Waku, K., Sugiura, T. J. Leukoc. Biol. (2004) [Pubmed]
  18. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Karsak, M., Cohen-Solal, M., Freudenberg, J., Ostertag, A., Morieux, C., Kornak, U., Essig, J., Erxlebe, E., Bab, I., Kubisch, C., de Vernejoul, M.C., Zimmer, A. Hum. Mol. Genet. (2005) [Pubmed]
  19. The effects of cannabinoids on the brain. Ameri, A. Prog. Neurobiol. (1999) [Pubmed]
  20. Endocannabinoids and cannabinoid receptor genetics. Onaivi, E.S., Leonard, C.M., Ishiguro, H., Zhang, P.W., Lin, Z., Akinshola, B.E., Uhl, G.R. Prog. Neurobiol. (2002) [Pubmed]
  21. Tuning the oviduct to the anandamide tone. Schuel, H. J. Clin. Invest. (2006) [Pubmed]
  22. Synthetic anti-BR3 antibodies that mimic BAFF binding and target both human and murine B cells. Lee, C.V., Hymowitz, S.G., Wallweber, H.J., Gordon, N.C., Billeci, K.L., Tsai, S.P., Compaan, D.M., Yin, J., Gong, Q., Kelley, R.F., Deforge, L.E., Martin, F., Starovasnik, M.A., Fuh, G. Blood (2006) [Pubmed]
  23. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. Shire, D., Carillon, C., Kaghad, M., Calandra, B., Rinaldi-Carmona, M., Le Fur, G., Caput, D., Ferrara, P. J. Biol. Chem. (1995) [Pubmed]
  24. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Gonsiorek, W., Lunn, C., Fan, X., Narula, S., Lundell, D., Hipkin, R.W. Mol. Pharmacol. (2000) [Pubmed]
  25. Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opioid receptors. Canals, M., Milligan, G. J. Biol. Chem. (2008) [Pubmed]
  26. Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. Mahadevan, A., Siegel, C., Martin, B.R., Abood, M.E., Beletskaya, I., Razdan, R.K. J. Med. Chem. (2000) [Pubmed]
  27. In silico patent searching reveals a new cannabinoid receptor. Baker, D., Pryce, G., Davies, W.L., Hiley, C.R. Trends Pharmacol. Sci. (2006) [Pubmed]
  28. Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules. Boger, D.L., Henriksen, S.J., Cravatt, B.F. Curr. Pharm. Des. (1998) [Pubmed]
  29. Orexin-1 Receptor-Cannabinoid CB1 Receptor Heterodimerization Results in Both Ligand-dependent and -independent Coordinated Alterations of Receptor Localization and Function. Ellis, J., Pediani, J.D., Canals, M., Milasta, S., Milligan, G. J. Biol. Chem. (2006) [Pubmed]
  30. Cannabinoid Receptor Agonist-induced Apoptosis of Human Prostate Cancer Cells LNCaP Proceeds through Sustained Activation of ERK1/2 Leading to G1 Cell Cycle Arrest. Sarfaraz, S., Afaq, F., Adhami, V.M., Malik, A., Mukhtar, H. J. Biol. Chem. (2006) [Pubmed]
  31. Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. Sipe, J.C., Arbour, N., Gerber, A., Beutler, E. J. Leukoc. Biol. (2005) [Pubmed]
  32. Stimulation of peripheral cannabinoid receptor CB2 induces MCP-1 and IL-8 gene expression in human promyelocytic cell line HL60. Jbilo, O., Derocq, J.M., Segui, M., Le Fur, G., Casellas, P. FEBS Lett. (1999) [Pubmed]
  33. Effect of the cannabinoid receptor ligand, WIN 55,212-2, on superoxide anion and TNF-alpha production by human mononuclear cells. Germain, N., Boichot, E., Advenier, C., Berdyshev, E.V., Lagente, V. Int. Immunopharmacol. (2002) [Pubmed]
  34. Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner. Paradisi, A., Pasquariello, N., Barcaroli, D., Maccarrone, M. J. Biol. Chem. (2008) [Pubmed]
  35. Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. Galve-Roperh, I., Rueda, D., Gómez del Pulgar, T., Velasco, G., Guzmán, M. Mol. Pharmacol. (2002) [Pubmed]
  36. FOXO1A differentially regulates genes of decidualization. Buzzio, O.L., Lu, Z., Miller, C.D., Unterman, T.G., Kim, J.J. Endocrinology (2006) [Pubmed]
  37. Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placenta. Park, B., Gibbons, H.M., Mitchell, M.D., Glassa, M. Placenta (2003) [Pubmed]
  38. Pharmacological actions of cannabinoids. Pertwee, R.G. Handbook of experimental pharmacology. (2005) [Pubmed]
  39. The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. Maccarrone, M., Di Rienzo, M., Battista, N., Gasperi, V., Guerrieri, P., Rossi, A., Finazzi-Agrò, A. J. Biol. Chem. (2003) [Pubmed]
  40. Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. Rossato, M., Ion Popa, F., Ferigo, M., Clari, G., Foresta, C. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  41. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Dyson, A., Peacock, M., Chen, A., Courade, J.P., Yaqoob, M., Groarke, A., Brain, C., Loong, Y., Fox, A. Pain (2005) [Pubmed]
  42. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Gérard, C.M., Mollereau, C., Vassart, G., Parmentier, M. Biochem. J. (1991) [Pubmed]
  43. Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. Mato, S., Del Olmo, E., Pazos, A. Eur. J. Neurosci. (2003) [Pubmed]
 
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