Hypocretin (orexin) receptor 2

Identifiers

External IDs

OMIM: 602393 MGI: 2680765 HomoloGene: 1168 IUPHAR: OX₂ ChEMBL: 4792 GeneCards: HCRTR2 Gene

Gene Ontology
Molecular function	• neuropeptide receptor activity • orexin receptor activity • peptide hormone binding
Cellular component	• plasma membrane • integral to plasma membrane
Biological process	• phospholipase C-activating G-protein coupled receptor signaling pathway • neuropeptide signaling pathway • synaptic transmission • feeding behavior
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 6:
55.04 – 55.15 Mb

Chr 9:
76.23 – 76.32 Mb

PubMed search

[1]

[2]

Orexin receptor type 2

Identifiers

Symbol

Orexin_rec2

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Orexin receptor type 2 (Ox2R or OX₂), also known as hypocretin receptor type 2, is a protein that in humans is encoded by the HCRTR2 gene.^[1]

1 Function
2 Ligands
- 2.1 Agonists
- 2.2 Antagonists
3 See also
4 References
5 External links
6 Further reading

Function [edit]

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.^[1]

Ligands [edit]

Agonists [edit]

Orexin-A
Orexin-B
SB-668,875

Antagonists [edit]

Almorexant - mixed OX_1/2 antagonist
SB-649,868 - mixed OX_1/2 antagonist
TCS-OX2-29 - selective OX₂ antagonist
1-(2,4-dibromophenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)urea (600x selective for OX₂ over OX₁)^[2]
(3,4-dimethoxyphenoxy)alkylamino acetamides ^[3]

References [edit]

^ ^a ^b "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2".
^ McAtee, LC; Sutton, SW; Rudolph, DA; Li, X; Aluisio, LE; Phuong, VK; Dvorak, CA; Lovenberg, TW et al. (2004). "Novel substituted 4-phenyl-1,3dioxanes: 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. |displayauthors= suggested (help)
^ Cole, AG; Stroke, IL; Qin, LY; Hussain, Z; Simhadri, S; Brescia, MR; Waksmunski, FS; Strohl, B et al. (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. |displayauthors= suggested (help)

External links [edit]

"Orexin Receptors: OX₂". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

Further reading [edit]

Flier JS, Maratos-Flier E (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.". Annu. Rev. Neurosci. 24: 429–58. doi:10.1146/annurev.neuro.24.1.429. PMID 11283317.
Hungs M, Mignot E (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 et al. (1998). "The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity". Proc. Natl. Acad. Sci. U.S.A. 95 (1): 322–7. doi:10.1073/pnas.95.1.322. PMC 18213. PMID 9419374.
Sakurai T, Amemiya A, Ishii M et al. (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 et al. (1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior". Cell 92 (5): 697. doi:10.1016/S0092-8674(02)09256-5. PMID 9527442.
Peyron C, Faraco J, Rogers W et al. (2000). "A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains". Nat. Med. 6 (9): 991–7. doi:10.1038/79690. PMID 10973318.
Wright GJ, Puklavec MJ, Willis AC et al. (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 (2001). "DNA Cloning Using In Vitro Site-Specific Recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Mazzocchi G, Malendowicz LK, Gottardo L et al. (2001). "Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade". J. Clin. Endocrinol. Metab. 86 (2): 778–82. doi:10.1210/jc.86.2.778. PMID 11158046.
Blanco M, López M, García-Caballero T et al. (2001). "Cellular localization of orexin receptors in human pituitary". J. Clin. Endocrinol. Metab. 86 (4): 1616–9. doi:10.1210/jc.86.4.1616. PMID 11297593.
Blanco M, López M, GarcIa-Caballero T et al. (2001). "Cellular localization of orexin receptors in human pituitary". J. Clin. Endocrinol. Metab. 86 (7): 3444–7. doi:10.1210/jc.86.7.3444. PMID 11443222.
Karteris E, Randeva HS, Grammatopoulos DK et al. (2001). "Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals". J. Clin. Endocrinol. Metab. 86 (9): 4512–9. doi:10.1210/jc.86.9.4512. PMID 11549701.
Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW (2001). "Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis". J. Clin. Endocrinol. Metab. 86 (10): 4808–13. doi:10.1210/jc.86.10.4808. PMID 11600545.
Olafsdóttir BR, Rye DB, Scammell TE et al. (2002). "Polymorphisms in hypocretin/orexin pathway genes and narcolepsy". Neurology 57 (10): 1896–9. PMID 11723285.
Blanco M, García-Caballero T, Fraga M et al. (2002). "Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas". Regul. Pept. 104 (1–3): 161–5. doi:10.1016/S0167-0115(01)00359-7. PMID 11830291.
Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.

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

Cell surface receptor: G protein-coupled receptors

Class A:
Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	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) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

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 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic
glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	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)

Class F:
Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

Neuropeptidergics

Cholecystokinin

CCK_A	Agonists: Cholecystokinin CCK-4 Antagonists: Asperlicin Proglumide Lorglumide Devazepide Dexloxiglumide

CCK_B	Agonists: Cholecystokinin CCK-4 Gastrin Antagonists: Proglumide CI-988

CRH

CRF₁	Agonists: Corticotropin releasing hormone Antagonists: Antalarmin CP-154,526 Pexacerfont

CRF₂	Agonists: Corticotropin releasing hormone

Galanin

GAL₁	Agonists: Galanin Galanin-like peptide Galmic Galnon

GAL₂	Agonists: Galanin Galanin-like peptide Galmic Galnon

GAL₃	Agonists: Galanin Galmic Galnon

Ghrelin

GnRH

MCH

MCH₁	Agonists: Melanin concentrating hormone Antagonists: ATC-0175 GW-803,430 NGD-4715 SNAP-7941 SNAP-94847

MCH₂	Agonists: Melanin concentrating hormone

Melanocortin

MC₁	Agonists: alpha-MSH Afamelanotide BMS-470,539 Bremelanotide Melanotan II Antagonists: Agouti signalling peptide

MC₂	Agonists: ACTH Cosyntropin Tetracosactide

MC₃	Agonists: alpha-MSH Bremelanotide Melanotan II

MC₄	Agonists: alpha-MSH Bremelanotide Melanotan II PF-00446687 THIQ Antagonists: Agouti-related peptide

MC₅	Agonists: alpha-MSH Melanotan II

Neuropeptide S

Agonists: Neuropeptide S
Antagonists: SHA-68

Neuropeptide Y

Y₁	Agonists: Neuropeptide Y Peptide YY Antagonists: BIBP-3226

Y₂	Agonists: Neuropeptide Y Peptide YY Antagonists: BIIE-0246

Y₄	Agonists: Neuropeptide Y Pancreatic polypeptide Peptide YY Antagonists: UR-AK49

Y₅	Agonists: Neuropeptide Y Peptide YY Antagonists: Lu AA-33810

Neurotensin

NTS₁	Agonists: Neurotensin Neuromedin N Antagonists: SR-48692 SR-142,948

NTS₂	Agonists: Neurotensin Antagonists: Levocabastine SR-142,948

Orexin

OX₁	Agonists: Orexin-A Antagonists: Almorexant SB-334,867 SB-408,124 SB-649,868 Suvorexant

OX₂	Agonists: Orexin-A Antagonists: Almorexant SB-649,868 Suvorexant TCS-OX2-29

Oxytocin

Tachykinin

NK₁	Agonists: Substance P Antagonists: Aprepitant Befetupitant Casopitant CI-1021 CP-96,345 CP-99,994 CP-122,721 Dapitant Ezlopitant FK-888 Fosaprepitant GR-203,040 GW-597,599 HSP-117 L-733,060 L-741,671 L-743,310 L-758,298 Lanepitant LY-306,740 Maropitant Netupitant NKP-608 Nolpitantium Orvepitant RP-67,580 SDZ NKT 343 Vestipitant Vofopitant

NK₂	Agonists: Neurokinin A Antagonists: GR-159,897 Ibodutant Saredutant

NK₃	Agonists: Neurokinin B Antagonists: Osanetant Talnetant

Vasopressin

V_1A	Agonists: Desmopressin Felypressin Ornipressin Terlipressin Vasopressin Antagonists: Conivaptan Demeclocycline Relcovaptan

V_1B	Agonists: Felypressin Ornipressin Terlipressin Vasopressin Antagonists: Demeclocycline Nelivaptan

V₂	Agonists: Desmopressin Ornipressin Vasopressin Antagonists: Conivaptan Demeclocycline Lixivaptan Mozavaptan Satavaptan Tolvaptan

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