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OX2 receptor

Family: Orexin receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 444 6p12.1 HCRTR2 hypocretin (orexin) receptor 2 33
Mouse 7 460 9q-D Hcrtr2 hypocretin (orexin) receptor 2 9
Rat 7 460 8q24 Hcrtr2 hypocretin (orexin) receptor 2 33
Previous and Unofficial Names
Hypocretin receptor type 2
OX2R
Hypocretin (orexin) receptor 2
hypocretin receptor 2
orexin receptor type 2
ox-2-R
ox2-R
mOX2aR
mOX2bR
mOXR2
Database Links
ChEMBL Target
Ensembl
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProt
Wikipedia
Search for 3D structures on the PDB
Search by keyword: Orexin receptors OX2 receptor
Natural/Endogenous Ligand(s)
orexin-A {Sp: Human, Mouse, Rat}
orexin-B {Sp: Human} , orexin-B {Sp: Mouse, Rat}
Rank order of potency (Human)
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[Ala11, D-Leu15]orexin-B Hs Full agonist 9.9 pEC50 3
orexin-A {Sp: Human, Mouse, Rat} Hs Full agonist 6.5 – 10.0 pEC50 17,20,29,33,38
orexin-B {Sp: Human} Hs Full agonist 6.5 – 10.0 pIC50 17,20,29,33,38
Agonist Comments
Efficacy values for agonists are highly depended on assay conditions
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]SB-674042 Hs Antagonist 6.9 pKd 22,25
MK-6096 Hs Antagonist 9.5 pKi 42
MK-4305 Hs Antagonist 9.46 pKi 11
N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide Hs Antagonist 9.0 pKi 24
SB-649868 Hs Antagonist 8.9 pKi 12
1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea Hs Antagonist 7.9 – 8.6 pKi 26
N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Hs Antagonist 7.4 pKi 15
1-(2-bromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea Hs Antagonist 6.8 – 7.1 pKi 26
SB-408124 Hs Antagonist 5.7 – 6.0 pKi 22,25
SB-334867 Hs Antagonist 5.2 – 6.3 pKi 25,30
ACT-078573 Hs Antagonist 8.1 pIC50 6
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
Gi/Go family
Gq/G11 family
G protein (identity unknown)
Adenylate cyclase stimulation
Adenylate cyclase inhibition
Phospholipase C stimulation
Other - See Comments
Comments:  Transduction via the Gs family leads to adenylyl cyclase stimulation; via the Gi family to adenylyl cyclase inhibition and via the Gq family to phospholipase C stimulation. Tranduction by an unknown mechanism leads to Ca2+ influx/stimulation of non-selective cation channels
References:  2,17,20,33,38,44
Tissue Distribution
Pituitary: corticotroph cells.
Species:  Human
Technique:  Immunohistochemistry.
References:  5
Lymph node > bone marrow, spleen > thymus > lung > liver > kidney > spinal cord.
Species:  Mouse
Technique:  RT-PCR.
References:  19
OX: brain, lung, spleen, testis.
OX: skeletal muscle, testis, spleen > brain, lung > liver, kidney.
Species:  Mouse
Technique:  PCR.
References:  9
Adrenal medulla.
Species:  Rat
Technique:  RT-PCR and immunohistrochemistry.
References:  23
Olfactory system: olfactory mucosa (olfactory epithelium and lamina propria) > olfactory bulb, anterior olfactory nuclei and piriform cortex, hypothalamic and amygdala nuclei.
Species:  Rat
Technique:  immunocytochemistry.
References:  8
Brainstem: lateral reticular field (LRt) and the nucleus of the solitary tract (NTS).
Species:  Rat
Technique:  in situ hybridisation.
References:  37
CNS: highest levels found in the cerebral cortex, nucleus accumbens, subthalamic and paraventricular thalamic nuclei, anterior pretectal nucleus.
Species:  Rat
Technique:  in situ hybridisation.
References:  39
Tuberomammillary (TM) neurons in the hypothalamus.
Species:  Rat
Technique:  RT-PCR.
References:  14
Pancreatic islets.
Species:  Rat
Technique:  RT-PCR.
References:  28
Pineal gland.
Species:  Rat
Technique:  RT-PCR.
References:  27
CNS: highest levels found in the brainstem, hypothalamus, thalamus > dorsal root ganglia.
Species:  Rat
Technique:  RT-PCR.
References:  10
CNS: highest levels found in the cerebral neocortex, basal ganglia, hippocampal formation, hypothalamus, thalamus, midbrain, reticular formation.
Species:  Rat
Technique:  Immunohistochemistry.
References:  10
Tissue Distribution Comments
NB: due to issues surrounding antibody selectivity, mRNA expression patterns provide important confirmatory results.
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of adenylyl cyclase and phospholipase C activation and Ca2+ elevation in HEK293 cell line transfected with OX2.
Species:  Human
Tissue:  HEK293 cells
Response measured:  cAMP and inositol phosphate accumulation, Ca2+ elevation
References:  31,38
Measurement of membrane conductance in tuberomammillary (TM) neurons endogenously expressing the OX2 receptor.
Species:  Rat
Tissue:  TM neurons.
Response measured:  Supression of GIRK current.
References:  17
Measurement of cAMP levels in a nerve-like BIM cell line transfected with the OX2 receptor.
Species:  Rat
Tissue:  BIM cell line.
Response measured:  PTX-sensitive inhibition of cAMP accumulation.
References:  44
Measurement of Ca2+ levels in CHO cells transfected with the OX2 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  (PLC-mediated) release of Ca2+ from intracellular stores followed by Ca2+ influx.. Possibly also receptor-operated Ca2+ influx
References:  2,18,33,36
Measurement of Ca2+ levels in a nerve-like BIM cell line transfected with the OX2 receptor.
Species:  Rat
Tissue:  BIM cell line.
Response measured:  PTX-insensitive increase in [Ca2+].
References:  44
Measurement of membrane conductance in HEK 293 cells transfected with the OX2 receptor and GIRK channels.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Biphasic response: Initial phase of GIRK activation (both PTX-sensitive and insensitive) followed by long-lasting GIRK inhibition (PTX-insensitive only).
References:  17
Orexin-induced cell death in CHO cells transfected with the OX2 receptor.
Species:  Human
Tissue:  CHO
Response measured:  Cell death
References:  40
Activation of ERK and p38 MAPK pathways in HEK cells transfected with the OX2 receptor.
Species:  Human
Tissue:  HEK
Response measured:  Stimulation of ERK and p38 phosphorylation (Western blotting)
References:  40
Physiological Functions
Stimulation of food intake.
Species:  Rat
Tissue:  In vivo.
References:  33
Inhibition of β-adrenoceptor-induced melatonin secretion and N-acetlytransferase (NAT) activity.
Species:  Rat
Tissue:  Dissociated pinealocytes.
References:  27
Excitation of neurons known to contribute to wakefulness.
Species:  Rat
Tissue:  Tuberomammillary (TM) nuclei from histaminergic neurons..
References:  4,14
Stimulation of noradrenaline release (unknown as to whether this via OX1 or OX2).
Species:  Rat
Tissue:  Cerebrocortical slices.
References:  16
Excitation of GABAergic neurons.
Species:  Rat
Tissue:  Septohippocampal GABAergic neurons.
References:  43
Neuronal excitation of GABAergic neurones via the Na-Ca exchanger.
Species:  Mouse
Tissue:  Arcuate nucleus (ARC) neurons.
References:  7
Supression of GH secretion (it is unclear as to whether this is mediated via the OX1 or OX2 receptor).
Species:  Rat
Tissue:  In vivo.
References:  34
Excitation of neurons known to be involved in the control of motivated behaviors.
Species:  Rat
Tissue:  Paraventricular nuclei of the thalamus (PVT).
References:  21
Increase in wake duration and decrease in REM and non-REM sleep.
Species:  Rat
Tissue:  In vivo.
References:  1
Excitation of neurons known to contribute to wakefulness.
Species:  Rat
Tissue:  Basal forebrain (BF) cholinergic neurons.
References:  13
Ethanol induced self-administration, place preference and behavioral reinstatement blocked by selective OX2 receptor antagonist, JNJ-10397049
Species:  Rat
Tissue:  Systemic (subcutaneous administration)
References:  35
Physiological Consequences of Altering Gene Expression
OX2 receptor knockout mice exhibit disrupted wakefulness, abnormal attacks of non-REM sleep and elimination of orexin-evoked excitation of histaminergic neurons in the hypothalamus.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  41
Physiological Consequences of Altering Gene Expression Comments
OX1 Gene disruption does not appear ro result in physiological problems
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Hcrtr2tm1Ywa Hcrtr2tm1Ywa/Hcrtr2tm1Ywa
involves: 129S6/SvEvTac * C57BL/6J
MGI:2680765  MP:0001501 abnormal sleep pattern PMID: 12797957 
Hcrtr2tm1Ywa Hcrtr2tm1Ywa/Hcrtr2tm1Ywa
involves: 129S6/SvEvTac * C57BL/6J
MGI:2680765  MP:0005279 narcolepsy PMID: 12797957 
Biologically Significant Variants
The single nucleotide polymorphism of 1246 G -> A is associated with a 5 fold higher risk of developing cluster headaches (CHs).
Type:  Single nucleotide polymorphism.
Species:  Human
References:  32
Two C-terminal splice variants of the mouse OX2 receptor have been found, OX (443 amino acids) and OX (460 amino acids), with similar orexin A and orexin B binding properties.
Orexin B produced a higher IP3 formation in OX than OX, whereas orexin A produced equal amounts of IP3 formation in both variants.
The OX variant is not found in skeletal muscle or the kidney and is upregulated in response to food deprivation.
Type:  Splice variants.
Species:  Mouse
References:  9

REFERENCES

To cite this database page, please use the following:

Christopher J. Winrow, Paul Coleman, Luis de Lecea, Thomas Kilduff, Jyrki P. Kukkonen, Rod Porter, John Renger, Jerome M Siegel, Gregor Sutcliffe, Neil Upton.
Orexin receptors: OX2 receptor. Last modified on 15/02/2013. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=322.


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