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0  structures 97  species 0  interactions 107  sequences 2  architectures

Family: Orexin_rec2 (PF03827)

Summary: Orexin receptor type 2

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Hypocretin (orexin) receptor 2". More...

Hypocretin (orexin) receptor 2 Edit Wikipedia article

HCRTR2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HCRTR2, OX2R, Hypocretin (orexin) receptor 2, hypocretin receptor 2
External IDs MGI: 2680765 HomoloGene: 1168 GeneCards: HCRTR2
Gene location (Human)
Chromosome 6 (human)
Chr. Chromosome 6 (human)[1]
Chromosome 6 (human)
Genomic location for HCRTR2
Genomic location for HCRTR2
Band 6p12.1 Start 55,106,460 bp[1]
End 55,282,620 bp[1]
RNA expression pattern
PBB GE HCRTR2 207393 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001526

NM_198962

RefSeq (protein)

NP_001517

NP_945200

Location (UCSC) Chr 6: 55.11 – 55.28 Mb Chr 9: 76.23 – 76.32 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Orexin receptor type 2
Identifiers
Symbol Orexin_rec2
Pfam PF03827
InterPro IPR004060

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]

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.[6]

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]

Ligands

Agonists

Antagonists

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000137252 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032360 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ a b "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2". 
  6. ^ Liszewski, Kathy (1 October 2015). "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News. 35 (17): 16. 
  7. ^ McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, Dvorak CA, Lovenberg TW, Carruthers NI, Jones TK (Aug 2004). "Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists". Bioorganic & Medicinal Chemistry Letters. 14 (16): 4225–9. doi:10.1016/j.bmcl.2004.06.032. PMID 15261275. 
  8. ^ Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, Lemaire W, Bruno JG, Harrell CM, Garson SL, Gotter AL, Fox SV, Stevens J, Tannenbaum PL, Prueksaritanont T, Cabalu TD, Cui D, Stellabott J, Hartman GD, Young SD, Winrow CJ, Renger JJ, Coleman PJ (Feb 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): 311–22. doi:10.1002/cmdc.201300447. PMID 24376006. 
  9. ^ Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, Cabalu TD, Stevens J, Brunner J, Tannenbaum PL, Garson SL, Savitz AT, Harrell CM, Gotter AL, Winrow CJ, Renger JJ, Coleman PJ (Jun 2015). "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters. 25 (12): 2488–92. doi:10.1016/j.bmcl.2015.04.066. PMID 25981685. 
  10. ^ Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, Waksmunski FS, Strohl B, Tellew JE, Williams JP, Saunders J, Appell KC, Henderson I, Webb ML (Oct 2008). "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5420–3. doi:10.1016/j.bmcl.2008.09.038. PMID 18815029. 
  11. ^ Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, Yoshikubo S, Hirai K, Marui S (Nov 2011). "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 21 (21): 6414–6. doi:10.1016/j.bmcl.2011.08.093. PMID 21917455. 

Further reading

  • Flier JS, Maratos-Flier E (Feb 1998). "Obesity and the hypothalamus: novel peptides for new pathways". Cell. 92 (4): 437–40. doi:10.1016/S0092-8674(00)80937-X. PMID 9491885. 
  • 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: 429–58. 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. 
  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (Jan 1998). "The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity". Proceedings of the National Academy of Sciences of the United States of America. 95 (1): 322–7. doi:10.1073/pnas.95.1.322. PMC 18213Freely accessible. PMID 9419374. 
  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (Feb 1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior" (PDF). Cell. 92 (4): 573–85. doi:10.1016/S0092-8674(00)80949-6. PMID 9491897. 
  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (Mar 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, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E (Sep 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): 991–7. doi:10.1038/79690. PMID 10973318. 
  • Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, Barclay AN (Aug 2000). "Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function". Immunity. 13 (2): 233–42. doi:10.1016/S1074-7613(00)00023-6. PMID 10981966. 
  • Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948Freely accessible. PMID 11076863. 
  • Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG (Feb 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): 778–82. doi:10.1210/jc.86.2.778. PMID 11158046. 
  • Blanco M, López M, García-Caballero T, Gallego R, Vázquez-Boquete A, Morel G, Señarís R, Casanueva F, Diéguez C, Beiras A (Apr 2001). "Cellular localization of orexin receptors in human pituitary". The Journal of Clinical Endocrinology and Metabolism. 86 (4): 1616–9. doi:10.1210/jc.86.4.1616. PMID 11297593. 
  • Blanco M, López M, GarcIa-Caballero T, Gallego R, Morel G, SeñarIs R, Casanueva F, Diéguez C, Beiras A (Jul 2001). "Cellular localization of orexin receptors in human pituitary". The Journal of Clinical Endocrinology and Metabolism. 86 (7): 1616–9. doi:10.1210/jc.86.7.3444. PMID 11443222. 
  • Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW (Sep 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): 4512–9. doi:10.1210/jc.86.9.4512. PMID 11549701. 
  • Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW (Oct 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): 4808–13. doi:10.1210/jc.86.10.4808. PMID 11600545. 
  • Olafsdóttir BR, Rye DB, Scammell TE, Matheson JK, Stefánsson K, Gulcher JR (Nov 2001). "Polymorphisms in hypocretin/orexin pathway genes and narcolepsy". Neurology. 57 (10): 1896–9. doi:10.1212/wnl.57.10.1896. PMID 11723285. 
  • Blanco M, García-Caballero T, Fraga M, Gallego R, Cuevas J, Forteza J, Beiras A, Diéguez C (Mar 2002). "Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas". Regulatory Peptides. 104 (1-3): 161–5. doi:10.1016/S0167-0115(01)00359-7. PMID 11830291. 
  • Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA (Dec 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241Freely accessible. PMID 12477932. 

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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Orexin receptor". More...

Orexin receptor Edit Wikipedia article

hypocretin (orexin) receptor 1
Identifiers
Symbol HCRTR1
Entrez 3061
HUGO 4848
OMIM 602392
RefSeq NM_001525
UniProt O43613
Other data
Locus Chr. 1 p33
hypocretin (orexin) receptor 2
Identifiers
Symbol HCRTR2
Entrez 3062
HUGO 4849
OMIM 602393
RefSeq NM_001526
UniProt O43614
Other data
Locus Chr. 6 p11-q11
Orexin receptor type 2
Identifiers
Symbol Orexin_rec2
Pfam PF03827
InterPro IPR004060

The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (HCRTR1, HCRTR2).[1]

Both orexin receptors exhibit a similar pharmacology - the 2 orexin peptides, orexin-A and orexin-B, bind to both receptors and, in each case, agonist binding results in an increase in intracellular calcium levels. However, orexin-B shows a 10-fold selectivity for orexin receptor type 2, whilst orexin-A is equipotent at both receptors.[2]

Several orexin receptor antagonists are in development for potential use in sleep disorders. [3]

Synthetic ligands

Several drugs[4] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. No neuropeptide agonists are yet available, although synthetic Orexin-A polypeptide has been made available as a nasal spray and tested on monkeys. One non-peptide antagonist is currently available in the U.S., Merck's suvorexant (Belsomra),;[5] two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials.[6] Another drug in development, almorexant (ACT-078573) by Actelion, was abandoned due to adverse effects.

Most ligands acting on the orexin system so far are polypeptides modified from the endogenous agonists Orexin-A and Orexin-B, however there are some subtype-selective non-peptide antagonists available for research purposes.

  • SB-334,867 – selective OX1 antagonist
  • SB-408,124 – selective OX1 antagonist
  • TCS-OX2-29 – selective OX2 antagonist
  • EMPA (N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) – selective OX2 antagonist
  • RTIOX-276 – selective OX1 antagonist

References

  1. ^ Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG (2006). "Orexins in the regulation of the hypothalamic-pituitary-adrenal axis". Pharmacol. Rev. 58 (1): 46–57. doi:10.1124/pr.58.1.4. PMID 16507882. 
  2. ^ Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F (September 1999). "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR". Br. J. Pharmacol. 128 (1): 1–3. doi:10.1038/sj.bjp.0702780. PMC 1571615Freely accessible. PMID 10498827. 
  3. ^ Yin J, Mobarec JC, Kolb P, Rosenbaum DM (December 2014). "Crystal Structure of the Human Ox2 Orexin Receptor Bound to the Insomnia Drug Suvorexant". Nature. 519: 247–250. doi:10.1038/nature14035. PMID 25533960. 
  4. ^ Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, Hallett D, Manikowski DP, Pal S, Reifegerste R, Slack M, Law R (2012). "Study of Human Orexin-1 and -2 G-Protein-Coupled Receptors with Novel and Published Antagonists by Modeling, Molecular Dynamics Simulations, and Site-Directed Mutagenesis". Biochemistry. 51 (15): 3178–3197. doi:10.1021/bi300136h. PMID 22448975. 
  5. ^ Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ (2011). "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder". Organic Process Research & Development. 15 (2): 367–375. doi:10.1021/op1002853. 
  6. ^ Hoch M, van Gorsel H, van Gerven J, Dingemanse J (Sep 2014). "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". J Clin Pharmacol. 54: 979–86. doi:10.1002/jcph.297. PMID 24691844. 

External links

This article incorporates text from the public domain Pfam and InterPro IPR004060


This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Orexin receptor type 2 Provide feedback

No Pfam abstract.

This tab holds annotation information from the InterPro database.

InterPro entry IPR004060

The neuropeptide hormone orexin stimulates appetite and food consumption [PUBMED:9656726], and is found in the hypothalamus, which has been shown to be the 'feeding centre' and plays a central role in the integrated control of feeding and energy homeostasis [PUBMED:9491897]. It also has a prominent role in promoting wakefulness [PUBMED:10458611, PUBMED:10615891, PUBMED:10481909]. The orexin receptor (also referred to as the hypocretin receptor) is a rhodopsin-like G protein-coupled receptor that binds orexin. There are two subtypes; orexin receptor 1 (OX1) and orexin receptor 2 (OX2) [PUBMED:16507882].

This entry represents Orexin receptor 2, which is found throughout vertebrates and, like OX1, is expressed in brainstem and striatal nuclei, with additional expression in arousal promoting histaminergic nuclei [PUBMED:9821961, PUBMED:21216246, PUBMED:11370008]. Both Orexin-A and B have nearly equal affinity for OX2 [PUBMED:9491897], and stimulate intracellular calcium levels through OX2-mediated induction of Gq and phospholipase C activity, but is also capable of activating Gs, Gi, and potentially ion channels [PUBMED:10498827, PUBMED:12208495, PUBMED:11600545, PUBMED:11600545]. The OX2 receptor predominantly mediate the control of arousal induced by orexin neuropeptides [PUBMED:12797957, PUBMED:10458611].

Gene Ontology

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(339)
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(34)
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(4)
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(107)
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(144)
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(339)
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(0)
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(10)
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(34)
RP55
(85)
RP75
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  Seed
(4)
Full
(107)
Representative proteomes UniProt
(144)
NCBI
(339)
Meta
(0)
RP15
(10)
RP35
(34)
RP55
(85)
RP75
(106)
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Curation and family details

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Seed source: PRINTS
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Griffiths-Jones SR
Number in seed: 4
Number in full: 107
Average length of the domain: 54.20 aa
Average identity of full alignment: 67 %
Average coverage of the sequence by the domain: 12.48 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 28.8 27.8
Noise cut-off 24.1 22.4
Model length: 57
Family (HMM) version: 13
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