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OX1 receptor

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Target not currently curated in GtoImmuPdb

Target id: 321

Nomenclature: OX1 receptor

Family: Orexin receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 425 1p35.2 HCRTR1 hypocretin receptor 1 84
Mouse 7 416 4 D2.2 Hcrtr1 hypocretin (orexin) receptor 1 17,84
Rat 7 416 5q36 Hcrtr1 hypocretin receptor 1 84
Previous and Unofficial Names Click here for help
Hctr1 | hypocretin receptor 1 | orexin receptor type 1 | OX1R
Database Links Click here for help
Specialist databases
GPCRdb ox1r_human (Hs), ox1r_rat (Rn)
Other databases
Alphafold O43613 (Hs), P58307 (Mm), P56718 (Rn)
ChEMBL Target CHEMBL5113 (Hs), CHEMBL2434819 (Mm), CHEMBL1075232 (Rn)
Ensembl Gene ENSG00000121764 (Hs), ENSMUSG00000028778 (Mm), ENSRNOG00000013838 (Rn)
Entrez Gene 3061 (Hs), 230777 (Mm), 25593 (Rn)
Human Protein Atlas ENSG00000121764 (Hs)
KEGG Gene hsa:3061 (Hs), mmu:230777 (Mm), rno:25593 (Rn)
OMIM 602392 (Hs)
Pharos O43613 (Hs)
RefSeq Nucleotide NM_001525 (Hs), NM_198959 (Mm), NM_013064 (Rn)
RefSeq Protein NP_001516 (Hs), NP_945197 (Mm), NP_037196 (Rn)
SynPHARM 83546 (in complex with SB-674042)
6603 (in complex with suvorexant)
UniProtKB O43613 (Hs), P58307 (Mm), P56718 (Rn)
Wikipedia HCRTR1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structures of the human OX1 orexin receptor bound to selective and dual antagonists.
PDB Id:  4ZJ8
Ligand:  suvorexant
Resolution:  2.75Å
Species:  Human
References:  100
Image of receptor 3D structure from RCSB PDB
Description:  Structures of the human OX1 orexin receptor bound to selective and dual antagonists.
PDB Id:  4ZJC
Ligand:  SB-674042
Resolution:  2.83Å
Species:  Human
References:  100
Image of receptor 3D structure from RCSB PDB
Description:  Structure-based development of subtype-selective orexin 1 receptor antagonists
PDB Id:  6V9S
Ligand:  JH112
Resolution:  3.5Å
Species:  Human
References:  30
Natural/Endogenous Ligands Click here for help
orexin-A {Sp: Human, Mouse, Rat}
orexin-B {Sp: Human} , orexin-B {Sp: Mouse, Rat}
Potency order of endogenous ligands
orexin-A (HCRT, O43612) > orexin-B (HCRT, O43612) (for Ca2+ elevation, unclear/variable for other responses)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
orexin-A {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 6.5 – 10.2 pEC50 2,20,33,35,41-42,45,50,55,72,84,88,93-94
⤷ pEC50 6.5 – 10.2 [2,20,33,35,41-42,45,50,55,72,84,88,93-94]
(R)-YNT-3708 Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.1 pEC50 38
⤷ pEC50 8.1 (EC50 7.74x10-9 M) [38]
Description: Determined in a calcium mobilization assay
RTOXA-43 Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.6 pEC50 104
⤷ pEC50 7.6 (EC50 2.4x10-8 M) [104]
Description: Determined in a Ca2+ response assay.
orexin-B {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 5.8 – 9.2 pEC50 2,35,42,55,72,76,84,88,93
⤷ pEC50 5.8 – 9.2 [2,35,42,55,72,76,84,88,93]
danavorexton Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 6.6 – 8.4 pEC50 103
⤷ pEC50 6.6 – 8.4 The value determined depends on the response measured. [103]
[Ala11, D-Leu15]orexin-B Peptide Click here for species-specific activity table Hs Full agonist 6.1 – 7.3 pEC50 5,76
⤷ pEC50 6.1 – 7.3 [5,76]
Nag 26 Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.3 – 6.7 pEC50 68,78
⤷ pEC50 5.3 – 6.7 (EC50 5.011x10-6 – 1.99x10-7 M) [68,78]
YNT-185 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.6 pEC50 39,68
⤷ pEC50 5.6 (EC50 2.75x10-6 M) [39,68]
firazorexton Small molecule or natural product Click here for species-specific activity table Hs Agonist 4.8 pEC50 40
⤷ pEC50 4.8 (EC50 1.4x10-5 M) [40]
Description: In a calcium mobilization assay
compound 1 [PMID: 33547286] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 4.4 pEC50 37
⤷ pEC50 4.4 [37]
Agonist Comments
Efficacy values for agonists are highly dependent on cell type, assay conditions and the readout.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SB-649868 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 10.0 pKB 16
⤷ pKB 10.0 [16]
daridorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Clf Antagonist 9.5 pKB 79
⤷ pKB 9.5 [79]
SB-649868 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.3 pKB 16
⤷ pKB 9.3 [16]
suvorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 9.1 – 9.3 pKB 16,91
⤷ pKB 9.3 [16]
pKB 9.1 [91]
filorexant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 9.2 pKB 16
⤷ pKB 9.2 [16]
daridorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.8 – 9.3 pKB 91
⤷ pKB 8.8 – 9.3 [91]
suvorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 9.0 pKB 16
⤷ pKB 9.0 [16]
daridorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 9.0 pKB 79
⤷ pKB 9.0 [79]
suvorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.7 pKB 16
⤷ pKB 8.7 [16]
filorexant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.7 pKB 16
⤷ pKB 8.7 [16]
SB-649868 Small molecule or natural product Click here for species-specific activity table Mm Antagonist 8.3 pKB 16
⤷ pKB 8.3 [16]
TCS 1102 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.0 – 8.5 pKB 7,78
⤷ pKB 8.0 – 8.5 [7,78]
SB-334867 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.1 pKB 61
⤷ pKB 8.1 [61]
almorexant Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.9 – 8.2 pKB 16,91
⤷ pKB 8.2 [91]
pKB 7.9 [16]
SB-408124 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.9 pKB 62
⤷ pKB 7.9 (KB 1.26x10-8 M) [62]
CVN45502 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 pKB 87
⤷ pKB 7.9 (KB 1.26x10-8 M) [87]
almorexant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.8 pKB 16
⤷ pKB 7.8 [16]
ACT-462206 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.8 pKB 12
⤷ pKB 7.8 [12]
almorexant Small molecule or natural product Click here for species-specific activity table Mm Antagonist 7.6 pKB 16
⤷ pKB 7.6 [16]
filorexant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 7.6 pKB 16
⤷ pKB 7.6 [16]
ACT-335827 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.4 pKB 89
⤷ pKB 7.4 [89]
seltorexant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.3 pKB 10
⤷ pKB 6.3 [10]
seltorexant Small molecule or natural product Click here for species-specific activity table Rn Antagonist <6.0 pKB 10
⤷ pKB <6.0 (KB >1x10-6 M) [10]
JNJ-10397049 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.0 – 5.5 pKB 64,90
⤷ pKB 5.5 [64]
pKB 5.0 [90]
[3H]-almorexant Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.6 – 8.9 pKd 62-63
⤷ pKd 8.6 – 8.9 [62-63]
[3H]SB-674042 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.3 – 9.1 pKd 55,62-63
⤷ pKd 8.3 – 9.1 (Kd 5.03x10-9 – 7.4x10-10 M) [55,62-63]
[3H]-TCS 1102 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.2 pKd 16
⤷ pKd 8.2 [16]
SB-649868 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.1 – 9.6 pKi 16,19,21
⤷ pKi 9.1 – 9.6 [16,19,21]
pKi 9.1 (Ki 7.94x10-10 M) [21]
JH112 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 9.1 pKi 30
⤷ pKi 9.1 (Ki 7.2x10-10 M) [30]
suvorexant Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.7 – 9.3 pKi 16,19,67,77,91
⤷ pKi 9.2 [91]
pKi 8.7 – 9.3 (Ki 5.01x10-10 M) [16,19,67,77]
SB-674042 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.7 – 9.3 pKi 55,62
⤷ pKi 8.7 – 9.3 (Ki 1.99x10-9 – 7.9x10-10 M) 70–120-fold selective pro-OX1 [55,62]
daridorexant Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.8 pKi 77
⤷ pKi 8.8 (Ki 1.58x10-9 M) [77]
filorexant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.4 – 9.2 pKi 16,19,77,98
⤷ pKi 9.2 [77]
pKi 8.4 – 9.1 [16,19,98]
lemborexant Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.2 – 8.6 pKi 77,101
⤷ pKi 8.6 [77]
pKi 8.2 (Ki 6x10-9 M) [101]
Description: In a radioligand binding assay
almorexant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 – 8.5 pKi 62-63,91
⤷ pKi 8.3 – 8.5 [62-63,91]
ACT-462206 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.2 pKi 77
⤷ pKi 8.2 [77]
SB-410220 Small molecule or natural product Hs Antagonist 7.7 pKi 55
⤷ pKi 7.7 [55]
HTL6641 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.5 – 7.7 pKi 18,77
⤷ pKi 7.7 (Ki 2x10-8 M) [18]
pKi 7.5 [77]
Cp-1 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.6 pKi 62
⤷ pKi 7.6 (Ki 2.57x10-8 M) [62]
SB-334867 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.2 – 7.9 pKi 11,55,61-62,74,77
⤷ pKi 7.2 – 7.9 40–150-fold selective pro-OX1 [11,55,62,74,77]
pKi 7.4 [61]
SB-408124 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.0 – 7.5 pKi 11,62
⤷ pKi 7.5 (Ki 3.16x10-8 M) 32–65-fold selective pro-OX1 [62]
pKi 7.0 (Ki 1x10-7 M) [11]
SB-334867 Small molecule or natural product Ligand has a PDB structure Rn Antagonist 6.8 pKi 11
⤷ pKi 6.8 (Ki 1.44x10-7 M) [11]
LSN2424100 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.4 pKi 26
⤷ pKi 6.4 (Ki 3.93x10-7 M) [26]
SB-408124 Small molecule or natural product Ligand has a PDB structure Rn Antagonist 6.4 pKi 11
⤷ pKi 6.4 (Ki 4x10-7 M) [11]
seltorexant Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.2 pKi 10
⤷ pKi 6.2 (Ki 6.3x10-7 M) [10]
Description: In vitro radioligand binding assay
seltorexant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.1 pKi 10
⤷ pKi 6.1 (Ki 7.94x10-7 M) [10]
Description: In vitro radioligand binding assay
MK-1064 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.0 pKi 66,81
⤷ pKi 6.0 [66,81]
MK-1064 Small molecule or natural product Click here for species-specific activity table Clf Antagonist 5.9 pKi 66,81
⤷ pKi 5.9 [66,81]
MK-1064 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.8 pKi 81
⤷ pKi 5.8 (Ki 1.584x10-6 M) [81]
EMPA Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.3 – 6.1 pKi 61-62,77
⤷ pKi 6.1 (Ki 9x10-7 M) [61]
Description: [3H]SB 674042 displacement by EMPA from HEK293-hOX1 membrane preparations
pKi 6.0 [77]
pKi 5.3 (Ki 4.533x10-6 M) [62]
MK-3697 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 5.6 pKi 66
⤷ pKi 5.6 [66]
JNJ-10397049 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.3 – 5.8 pKi 64
⤷ pKi 5.3 – 5.8 [64]
MK-3697 Small molecule or natural product Click here for species-specific activity table Clf Antagonist 5.5 pKi 66
⤷ pKi 5.5 [66]
MK-3697 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.4 – 5.5 pKi 66,82
⤷ pKi 5.5 [66]
pKi 5.4 (Ki 3.6x10-6 M) [82]
MK-1064 Small molecule or natural product Click here for species-specific activity table Mm Antagonist 5.4 pKi 66,81
⤷ pKi 5.4 [66,81]
MK-3697 Small molecule or natural product Click here for species-specific activity table Mm Antagonist 5.4 pKi 66
⤷ pKi 5.4 [66]
compound 11 [PMID: 15261275] Small molecule or natural product Click here for species-specific activity table Hs Antagonist <5.3 pKi 64
⤷ pKi <5.3 (Ki >5.012x10-6 M) [64]
Description: Radioligand displacement assay using [125I]-orexin A as radio ligand.
CVN766 Small molecule or natural product Hs Antagonist 8.1 pIC50 27
⤷ pIC50 8.1 (IC50 8x10-9 M) [27]
View species-specific antagonist tables
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]orexin A (human, mouse, rat) Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - - - 50,75,84
⤷ Useful working concentration sub nM-low nM. [50,75,84]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Adenylyl cyclase stimulation
Adenylyl cyclase inhibition
Phospholipase C stimulation
Phospholipase A2 stimulation
Phospholipase D stimulation
Comments:  Association with the Gq family of transducers leads to phospholipase stimulation (e.g. phospholipase families A2, C and D) and Ca2+ elevation, and with the Gi family to inhibition and with the Gs family to stimulation, respectively, of adenylyl cyclase. Ca2+/non-selective cation influx also appears to rely on Gq. However, the signal transduction has not been investigated in detail in native neurons.
References:  2,33,35,42,49-51,53,57-58,60,65,71,84,88,93-94,96
Tissue Distribution Click here for help
Pituitary: somatotroph cells.
Species:  Human
Technique:  Immunohistochemistry.
References:  9
Retina: ganglion cells, photoreceptor cells > amacrine cells, inner and outer plexiform layers.
Species:  Human
Technique:  Immunohistochemistry.
References:  86
Lung, skeletal muscle, kidney, testis > spleen > brain, liver.
Species:  Mouse
Technique:  RT-PCR
References:  17
CNS: highest levels found in the locus coeruleus > olfactory nuclei, piriform cortex, dentate gyrus of the hippocampus, bed nucleus of the stria terminalis, anterodorsal, centrolateral, reticular and ventral posterior thalamic nuclei, zona incerta, arcuate, paraventricular and periventricular hypothalamic nuclei, supraoptic nucleus, suprachiasmatic nucleus, dorsal tegmental nucleus, cochlear nucleus complex, facial nucleus, olivary complex, spinal cord, dorsal root ganglia.
Species:  Rat
Technique:  Immunohistochemistry.
References:  31
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:  15
CNS: highest levels found in the ventromedial hypothalamic nucleus, tenia tecta, indusium griseum, septohippocampal nucleus, locus coeruleus.
Species:  Rat
Technique:  In situ hybridization.
References:  92
CNS: highest levels found in the hypothalamus, substantia nigra, thalamus.
Species:  Rat
Technique:  RT-PCR.
References:  31
Cerebral cortex, hippocampus, hypothalamus, several thalamic nuclei.
Species:  Rat
Technique:  Immunohistochemistry.
References:  6
Pancreatic islets.
Species:  Rat
Technique:  RT-PCR.
References:  70
Adrenal medulla.
Species:  Rat
Technique:  RT-PCR.
References:  59
Tissue Distribution Comments
For IHC studies, it is very important to note that selectivity issues have been raised regarding antibodies for the orexin receptors which may lead to false positive/negative results and as such, mRNA expression patterns provide important confirmatory results.
Expression Datasets Click here for help

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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 Click here for help
Ca2+ elevation in BIM hybridoma cells transfected with the OX1 receptor.
Species:  Rat
Tissue:  BIM cells
Response measured:  PTX-insensitive increase in [Ca2+].
References:  105
Measurement of membrane conductance in locus coeruleus (LC) neurons endogenously expressing OX1 receptors.
Species:  Rat
Tissue:  LC neurons
Response measured:  Suppression of GIRK current.
References:  33
Measurement of cAMP levels in CHO-K1 cells transfected with the OX1 receptor.
Species:  Human
Tissue:  CHO-K1 cells
Response measured:  Stimulation (Gs and protein kinase C) and inhibition (Gi) of cAMP accumulation.
References:  36,49-50
Activation of ERK, p38 and JNK pathways in CHO-K1 cells transfected with the OX1 receptor
Species:  Human
Tissue:  CHO-K1 cells
Response measured:  Stimulation of ERK, p38 and JNK phosphorylation, programmed cell death.
References:  3-4,46
Activation of phospholipase A2 and monoacylglycerol lipase-like enzyme-mediated arachidonic acid release in HEK293, CHO-K1 and neuro-2a cells transfected with the OX1 receptor
Species:  Human
Tissue:  HEK293, CHO-K1 and neuro-2a cells
Response measured:  Arachidonic acid and 2-arachidonoyl glycerol release, Ca2+ elevation
References:  73,93-94
Regulation of cell death and associated pathways in native and immortalised cell lines transfected to express the OX1 receptor
Species:  Human
Tissue:  CHO-S and -K1 and HT29-D4 cell lines, primary human colon carcinoma
Response measured:  Cell death
References:  4,25,83,95
Activation of phospholipase D activity in CHO cells transfected with the OX1 receptor
Species:  Human
Tissue:  CHO
Response measured:  Phospholipase D activity (PtdBut generation assay) etc.
References:  42,45,49-50
Activation of phospholipase C in CHO-K1 cells transfected with the OX1 receptor
Species:  Human
Tissue:  CHO-K1 cells
Response measured:  Inositol phosphate release, PIP2 hydrolysis, IP3 elevation, diacylglycerol release, monoacylglycerol generation
References:  41-42,49-50,58,94
Measurement of membrane conductance in HEK 293 cells transfected with the OX1 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:  33
Activation of phospholipase C and Ca2+ elevation in neuro-2a and PC12 cells transfected with the OX1 receptor
Species:  Human
Tissue:  neuro-2a, PC12 cells
Response measured:  Inositol phosphate release, Ca2+ elevation
References:  34
Ca2+ elevation in CHO-K1 cells transfected with the OX1 receptor.
Species:  Human
Tissue:  CHO-K1 cells
Response measured:  Increase in [Ca2+]i via receptor-operated Ca2+ influx, (phospholipase C-mediated) Ca2+ release and store-operated Ca 2+ influx
References:  49,52,56,58,84,88,93-94
Physiological Functions Click here for help
Modulation of pain; analgesic and anti-hyperalgesic effects against a variety of noxious stimuli.
Species:  Rat
Tissue:  In vivo.
References:  8,99
Modulation of feeding.
Species:  Rat
Tissue:  In vivo.
References:  29,80
Stimulation of water intake.
Species:  Rat
Tissue:  In vivo.
References:  54
Increase in respiratory drive.
Species:  Rat
Tissue:  Pre-Bötzinger-neurons and phrenic nuclei.
References:  102
Stimulation of behavioural arousal.
Species:  Rat
Tissue:  In vivo.
References:  22,44
Control of gastrointestinal function; modulation of gut motility and acid secretion.
Species:  Rat
Tissue:  In vivo.
References:  23-24
Regulation of haemodynamic responses; modulation of heart rate and blood pressure in anaesthetised rats.
Species:  Rat
Tissue:  In vivo.
References:  32
Modulation of rewarding behaviours and addiction.
Species:  Rat
Tissue:  In vivo.
References:  14,28
Facilitation of learning and memory. Targeted delivery of orexin-A to the dentate gyrus of anaesthetised rats produces an enhancement of LTP that is prevented by an OX1 receptor antagonist. Conversely, direct blockade of hippocampal OX1 receptors impairs spatial learning and memory in conscious rats.
Species:  Rat
Tissue:  In vivo.
References:  1,97
Enhancement of arousal and reduction in paradoxical and slow-wave sleep. Both an OX1 receptor-neutralising antibody and an OX1 receptor antagonist reverse the disruption of the sleep-wake cycle induced by centrally administered orexin-A.
Species:  Rat
Tissue:  In vivo.
References:  13
Panic: Activation of orexinergic neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding preproorexin (Hcrt) with RNAi, or systemic OX1 receptor antagonists, blocks the panic responses; (human and rat)
Species:  Human
Tissue:  In vivo.
References:  43,85
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Hcrtr1tm1Dgen Hcrtr1tm1Dgen/Hcrtr1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:2385650  MP:0002906 increased susceptibility to pharmacologically induced seizures
General Comments
No consequent differences in the molecular details of the signalling of the orexin receptor subtypes can be pointed out. In the CNS, both receptor subtypes regulate ion channel activity, most centrally leading to depolarization via activation of non-selective cation channels and inhibition of K+ channels [47,53,57]. Also, activation of Na+/Ca2+ exchanger has been reported. Orexin receptor activation has been implicated in modulation of synaptic plasticity. In native cells, cell lines and recombinant cells expressing heterologous orexin receptors, a wide set of molecular responses have been described. The immediate responses include activation of G proteins of Gq, Gi and Gs families and β-arrestin. Gq regulates at least receptor-operated Ca2+/non-selective cation influx and phospholipase C-mediated Ca2+ release, while Gi and Gs regulate adenylyl cyclase [48,50,53,57].
Orexin receptor subtypes form homo- and heteromeric complexes in recombinant systems. In addition, they are known to heteromerize with at least CB1 cannabinoid, κ opioid and CRF1 corticotropin receptors as well as with GPR103 [Reference: Kukkonen JP, Orexin/hypocretin Signaling, in Current Topics in Behavioral Neuroscience: Behavioral Neuroscience of Orexin/Hypocretin; ed. Andrew J Lawrence & Luis De Lecea, Springer; accepted for publication]. Little physiological significance has thus far been shown for this complex formation, except for a recent study showing complexes of OX1, CRF1 and σ-1 receptors, which operate in orexin regulation of dopamine release in vetral tegmental area [69].

References

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