Protein-coding gene in the species Homo sapiens
Protein family
Orexin receptor type 2 (Ox2R or OX2 ), also known as hypocretin receptor type 2 (HcrtR2 ), is a protein that in humans is encoded by the HCRTR2 gene .[ 5] CD200R1 which shares the alias OX2R but is a distinct, unrelated gene located on the human chromosome 3.[ 6]
Structure The structure of the receptor has been solved to 2.5 Å resolution as a fusion protein bound to suvorexant using lipid-mediated crystallization.[ 7]
Function OX2 is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with OX1 . OX2 binds both orexin A and orexin B neuropeptides. OX2 is involved in the central feedback mechanism that regulates feeding behaviour.[ 5] 2 signaling are resistant to high-fat diet-induced obesity.[ 8]
This receptor is activated by Hipocretin , which is a wake-promoting hypothalamic neuropeptide that acts as a critical regulator of sleep in animals as Zebrafish or Mammals . This protein has mutations in Astyanax mexicanus that reduces the sleep needs of the cavefish. [ 9]
Ligands
Agonists
Antagonists
See also
References
^ a b c GRCh38: Ensembl release 89: ENSG00000137252 – Ensembl , May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032360 – Ensembl , May 2017^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ a b "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2" .^ "Genecards CD200R1" . Retrieved 2024-07-17 .^ Liszewski K (1 October 2015). "Dissecting the Structure of Membrane Proteins" . Genetic Engineering & Biotechnology News 35 (17): 16. doi :10.1089/gen.35.07.09 . ^ Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, et al. (January 2009). "Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity" . Cell Metabolism . 9 (1): 64– 76. doi :10.1016/j.cmet.2008.10.010 . PMC 2630400 PMID 19117547 . ^ Warren WC, Boggs TE, Borowsky R, Carlson BM, Ferrufino E, Gross JB, et al. (March 2021). "A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution" . Nature Communications . 12 (1): 1447. Bibcode :2021NatCo..12.1447W . doi :10.1038/s41467-021-21733-z . PMC 7933363 PMID 33664263 . ^ a b "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 263 : International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF) . Who.int . Retrieved 2021-11-30 .^ a b WO application 2019027058 , Kajita, Yuichi; Mikami, Satoshi & Miyanohana, Yuhei et al., "Heterocyclic compound and use therof", published 2019-02-07, assigned to Takeda Pharmaceutical Company ^ a b Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, et al. (September 1999). "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR" . British Journal of Pharmacology . 128 (1): 1– 3. doi :10.1038/sj.bjp.0702780 . PMC 1571615 PMID 10498827 . ^ a b Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (January 2004). "Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor" . British Journal of Pharmacology . 141 (2): 340– 346. doi :10.1038/sj.bjp.0705610 . PMC 1574197 PMID 14691055 . ^ "Wave 1 Pipeline Market Opportunity Conference Call" (PDF) . Takeda Pharmaceutical Company Limited. 8 December 2020. Archived from the original (PDF) on 2021-10-20. TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20 ^ McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, et al. (August 2004). "Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists". Bioorganic & Medicinal Chemistry Letters . 14 (16): 4225– 4229. doi :10.1016/j.bmcl.2004.06.032 . PMID 15261275 . ^ Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, et al. (February 2014). "Discovery of 5-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3 -terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia". ChemMedChem . 9 (2): 311– 322. doi :10.1002/cmdc.201300447 . PMID 24376006 . S2CID 26114114 . ^ Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, et al. (June 2015). "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters . 25 (12): 2488– 2492. doi :10.1016/j.bmcl.2015.04.066 . PMID 25981685 . ^ Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, et al. (October 2008). "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters . 18 (20): 5420– 5423. doi :10.1016/j.bmcl.2008.09.038 . PMID 18815029 . ^ Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, et al. (November 2011). "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters . 21 (21): 6414– 6416. doi :10.1016/j.bmcl.2011.08.093 . PMID 21917455 .
Further reading
Flier JS, Maratos-Flier E (February 1998). "Obesity and the hypothalamus: novel peptides for new pathways" . Cell . 92 (4): 437– 440. doi :10.1016/S0092-8674(00)80937-X PMID 9491885 . S2CID 14768585 . Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001). "To eat or to sleep? Orexin in the regulation of feeding and wakefulness". Annual Review of Neuroscience . 24 : 429– 458. doi :10.1146/annurev.neuro.24.1.429 . PMID 11283317 . Hungs M, Mignot E (May 2001). "Hypocretin/orexin, sleep and narcolepsy". BioEssays . 23 (5): 397– 408. doi :10.1002/bies.1058 . PMID 11340621 . S2CID 541650 . de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. (January 1998). "The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity" . Proceedings of the National Academy of Sciences of the United States of America . 95 (1): 322– 327. Bibcode :1998PNAS...95..322D . doi :10.1073/pnas.95.1.322 PMC 18213 PMID 9419374 . Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. (February 1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior" . Cell . 92 (4): 573– 585. doi :10.1016/S0092-8674(00)80949-6 PMID 9491897 . S2CID 16294729 . Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. (March 1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior" . Cell . 92 (5): 1 page following 696. doi :10.1016/S0092-8674(02)09256-5 PMID 9527442 . Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. (September 2000). "A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains". Nature Medicine . 6 (9): 991– 997. doi :10.1038/79690 . PMID 10973318 . S2CID 18076282 . Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, et al. (August 2000). "Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function" . Immunity . 13 (2): 233– 242. doi :10.1016/S1074-7613(00)00023-6 PMID 10981966 . Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination" . Genome Research . 10 (11): 1788– 1795. doi :10.1101/gr.143000 . PMC 310948 PMID 11076863 . Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG (February 2001). "Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade" . The Journal of Clinical Endocrinology and Metabolism . 86 (2): 778– 782. doi :10.1210/jcem.86.2.7233 PMID 11158046 . Blanco M, López M, García-Caballero T, Gallego R, Vázquez-Boquete A, Morel G, et al. (April 2001). "Cellular localization of orexin receptors in human pituitary" . The Journal of Clinical Endocrinology and Metabolism . 86 (4): 1616– 1619. doi :10.1210/jcem.86.7.7433 PMID 11297593 . Blanco M, López M, GarcIa-Caballero T, Gallego R, Morel G, SeñarIs R, et al. (July 2001). "Cellular localization of orexin receptors in human pituitary" . The Journal of Clinical Endocrinology and Metabolism . 86 (7): 1616– 1619. doi :10.1210/jcem.86.7.7433 PMID 11443222 . Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW (September 2001). "Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals" . The Journal of Clinical Endocrinology and Metabolism . 86 (9): 4512– 4519. doi :10.1210/jcem.86.9.7849 PMID 11549701 . Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW (October 2001). "Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis" . The Journal of Clinical Endocrinology and Metabolism . 86 (10): 4808– 4813. doi :10.1210/jcem.86.10.7921 PMID 11600545 . Olafsdóttir BR, Rye DB, Scammell TE, Matheson JK, Stefánsson K, Gulcher JR (November 2001). "Polymorphisms in hypocretin/orexin pathway genes and narcolepsy". Neurology . 57 (10): 1896– 1899. doi :10.1212/wnl.57.10.1896 . PMID 11723285 . S2CID 38597998 . Blanco M, García-Caballero T, Fraga M, Gallego R, Cuevas J, Forteza J, et al. (March 2002). "Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas". Regulatory Peptides . 104 (1– 3): 161– 165. doi :10.1016/S0167-0115(01)00359-7 . PMID 11830291 . S2CID 30238394 . This article incorporates text from the United States National Library of Medicine , which is in the public domain .
