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14-September-2008 18:02:41 - receptor CB1 and CB2 structures. CB1 and CB2 structures. cannabinoid receptor 1 brain Identifiers Symbol CNR1 Alt. Symbols CNR Entrez 1268 HUGO 2159 OMIM 114610 RefSeq NM_033181 UniProt P21554 Other data Locus Chr. 6 q14-q15 cannabinoid receptor 2 macrophage Identifiers Symbol CNR2 Entrez 1269 HUGO 2160 OMIM 605051 RefSeq NM_001841 UniProt P34972 Other data Locus Chr. 1 p The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids or endocannabinoids depending on whether they come from external or internal endogenous sources, respectively. Contents 1 Classification 1.1 CB1 1.2 CB2 2 Signaling 2.1 Cardiovascular activity 2.2 Pain 3 Cannabinoid treatments 4 References 5 External links Classification There are currently two known subtypes, CB112 which is expressed mainly in the brain, but also in the lungs, liver and kidneys and CB2 which is mainly expressed in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptors3 that is, non-CB1 and non-CB2, which are expressed in endothelial cells and in the CNS. In 2007, the binding of several cannabinoids to a GPCR in the brain was described.4 The protein sequences of CB1 and CB2 receptors are about 44% similar5. In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. The affinity of an individual cannabinoid to each receptor determines the effect of that cannabinoid. Cannabinoids that bind more selectively to certain receptors are more desirable for medical usage. CB1 Main article: Cannabinoid receptor type 1 Cannabinoid receptor type 1 CB1 receptors are thought to be the most widely expressed G-protein coupled receptors in the brain. This is due 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. They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis,6 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.7 CB2 CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes, and are expressed on mouse pre-implantation embryos. It is also expressed on peripheral nerve terminals.In the brain, they are mainly expressed by microglial cells, where their role remains unclear. Signaling Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body endocannabinoids or introduced into the body as cannabis or a related synthetic compound. After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited 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.8 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. The hypotension in hemorrhaged rats was prevented by the CB1 antagonist SR 141716A. Recently the same group found that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR 141716A-sensitive anandamide receptor, distinct from the CB1 cannabinoid receptor, and that activation of such a receptor by an endocannabinoid, possibly anandamide, contributes to endotoxin-induced mesenteric vasodilation in vivo. The highly potent synthetic cannabinoid HU-210, as well as 2-AG, had no mesenteric vasodilator activity. Furthermore it was shown that mesenteric vasodilation by anandamide apparently has 2 components, one mediated by a SR 141716-sensitive non-CB1 receptor located on the endothelium and the other by an SR 141716A-resistant direct action on vascular smooth muscle. The production of 2-AG is enhanced in normal, but not in endothelium-denuded rat aorta on stimulation with Carbachol, an acetylcholine receptor agonist. 2-AG potently reduces blood pressure in rats and may represent an endothelium-derived hypotensive factor. 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. Cannabinoid treatments Cannabis sativa preparations have been known as therapeutic agents against various diseases for millennia.9 The native active constituent, Δ9-tetrahydrocannabinol Δ9-THC was found to be the principal mediator of the effects of cannabis.10 Synthetic Δ9-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients. U.S. Pat. No. 5,434,295 discloses a family of novel 4-phenyl pinene derivatives, and teaches how to use those compounds in pharmaceutical compositions useful for treating various pathological conditions associated with damage to the central nervous system. U.S. Pat. No. 4,282,248 discloses additional pinene derivatives. These patents do not mention that any of the disclosed compounds are selective for peripheral cannabinoid receptors. Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher affinity than to the CB1 receptor. Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB1/CB2 binding ratio 1000. The pharmacology of those known agonists has yet to be described. Certain tumors, especially gliomas, express CB2 receptors. Guzman and coworkers have shown that Δ9-tetrahydrocannabinol and WIN-55,212-2, two non-selective cannabinoid agonists, induce the regression or eradication of malignant brain tumors in rats and mice.11 CB2 selective agonists are effective in the treatment of pain, various inflammatory diseases in different animal models,12 13 osteoporosis13 and atherosclerosis.14 CB1 selective antagonists are used for weight reduction and smoking cessation see Rimonabant. Activation of CB1 provides neuroprotection after brain injury.15 References ^ Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI 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 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. ^ Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G 2005. Evidence for novel cannabinoid receptors. Pharmacol. Ther. 106 2: 133-45. doi:10.1016/j.pharmthera.2004.11.005. PMID 15866316. ^ Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ 2007. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152 7: 1092-101. doi:10.1038/sj.bjp.0707460. PMID 17876302. ^ Munro S, Thomas KL, Abu-Shaar M 1993. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365 6441: 61-65. PMID 7689702. ^ 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. ^ a b Demuth DG, Molleman A 2006. Cannabinoid signalling. Life Sci. 78 6: 549-63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430. ^ Pacher P, Bátkai S, Kunos G 2006. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58 3: 389-462. doi:10.1124/pr.58.3.2. PMID 16968947. ^ Gaoni Y, Mechoulam R 1964. Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86 8: 1646-1647. doi:10.1021/ja01062a046. ^ Galve-Roperh I, Sánchez C, Cortés ML, del Pulgar TG, Izquierdo M, Guzmán M 2000. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6 3: 313-9. doi:10.1038/73171. PMID 10700234. ^ Whiteside GT, Lee GP, Valenzano KJ 2007. The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr. Med. Chem. 14 8: 917-36. doi:10.2174/092986707780363023. PMID 17430144. ^ a b Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I 2006. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc. Natl. Acad. Sci. U.S.A. 103 3: 696-701. doi:10.1073/pnas.0504187103. PMID 16407142. ^ Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F 2005. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434 7034: 782-6. doi:10.1038/nature03389. PMID 15815632. ^ 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. External links IUPHAR GPCR Database - Cannabinoid Receptors The Endocannabinoid System Network ECSN - CB1 receptor MeSH Cannabinoid+Receptors 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 Retrieved from http://en..org/wiki/Cannabinoid_receptor Categories: Genes on chromosome 6 | Genes on chromosome 1 | G protein coupled receptorsHidden category: Protein pages needing a picture Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Italiano Suomi This page was last modified on 6 September 2008, at 10:50
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