Hypocretin (orexin) receptor 2

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] It should not be confused for the protein CD200R1 which shares the alias OX2R but is a distinct, unrelated gene located on the human chromosome 3.^[6]

HCRTR2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4S0V
Identifiers
Aliases	HCRTR2, OX2R, Hypocretin (orexin) receptor 2, hypocretin receptor 2, ORXR2, OXR2
External IDs	OMIM: 602393; MGI: 2680765; HomoloGene: 1168; GeneCards: HCRTR2; OMA:HCRTR2 - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p12.1 Start 55,106,460 bp[1] End 55,282,617 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 D Start 76,133,162 bp[2] End 76,231,138 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle prefrontal cortex Pons Hypothalamus Achilles tendon gonad Brodmann area 9 ventricular zone superior vestibular nucleus ganglionic eminence Top expressed in morula embryo spinal ganglia pontine nuclei dentate gyrus of hippocampal formation granule cell primary visual cortex neural tube superior frontal gyrus blastocyst cerebellar cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptide hormone binding peptide binding G protein-coupled receptor activity signal transducer activity neuropeptide receptor activity orexin receptor activity Cellular component integral component of membrane plasma membrane membrane integral component of plasma membrane Biological process phospholipase C-activating G protein-coupled receptor signaling pathway cellular response to hormone stimulus regulation of circadian sleep/wake cycle, sleep circadian sleep/wake cycle process signal transduction response to peptide chemical synaptic transmission regulation of cytosolic calcium ion concentration regulation of circadian sleep/wake cycle, wakefulness neuropeptide signaling pathway feeding behavior G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3062 387285 Ensembl ENSG00000137252 ENSMUSG00000032360 UniProt O43614 P58308 RefSeq (mRNA) NM_001526 NM_001384272 NM_198962 NM_001364551 RefSeq (protein) NP_001517 NP_945200 NP_001351480 Location (UCSC) Chr 6: 55.11 – 55.28 Mb Chr 9: 76.13 – 76.23 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Orexin receptor type 2
Identifiers
Symbol	Orexin_rec2
Pfam	PF03827
InterPro	IPR004060
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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] Mice with enhanced OX₂ 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

• Danavorexton (TAK-925) – selective OX₂ receptor agonist
• Firazorexton – selective OX₂ receptor agonist^[10][11]
• Orexins – dual OX₁ and OX₂ receptor agonists
  • Orexin-A – approximately equipotent at the OX₁ and OX₂ receptors^[12][13]
  • Orexin-B – approximately 5- to 10-fold selectivity for the OX₂ receptor over the OX₁ receptor^[12][13]
• Oveporexton
• SB-668875 – selective OX₂ receptor agonist
• Suntinorexton – selective OX₂ receptor agonist^[10][11]
• TAK-861 – selective OX₂ receptor agonist^[14]

Antagonists

• Almorexant - Dual OX₁ and OX₂ antagonist
• Daridorexant (nemorexant) - Dual OX₁ and OX₂ antagonist
• EMPA - Selective OX₂ antagonist
• Filorexant - Dual OX₁ and OX₂ antagonist
• JNJ-10397049 (600x selective for OX₂ over OX₁)^[15]
• Lemborexant - Dual OX₁ and OX₂ antagonist
• MK-1064 - Selective OX₂ antagonist^[16]
• MK-8133 - Selective OX₂ antagonist^[17]
• SB-649,868 - Dual OX₁ and OX₂ antagonist
• Seltorexant - Selective OX₂ antagonist
• Suvorexant - Dual OX₁ and OX₂ antagonist
• TCS-OX2-29 - Selective OX₂ antagonist
• (3,4-dimethoxyphenoxy)alkylamino acetamides^[18]
• Compound 1m - Selective OX₂ antagonist^[19]

See also

• Orexin receptor