Gene Symbol: Hcrtr2
Description: hypocretin (orexin) receptor 2
Alias: OX2R, mOX2aR, mOX2bR, mOXR2, orexin receptor type 2, hypocretin receptor type 2, orexin receptor type-2a, ox-2-R, ox2-R
Species: mouse
Products:     Hcrtr2

Top Publications

  1. Willie J, Chemelli R, Sinton C, Tokita S, Williams S, Kisanuki Y, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;38:715-30 pubmed
    ..Both OX2R(-/-) and orexin(-/-) mice are similarly affected with behaviorally abnormal attacks of non-REM sleep ("sleep ..
  2. Kalogiannis M, Grupke S, Potter P, Edwards J, Chemelli R, Kisanuki Y, et al. Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons. Eur J Neurosci. 2010;32:130-42 pubmed publisher
  3. Chen J, Randeva H. Genomic organization of mouse orexin receptors: characterization of two novel tissue-specific splice variants. Mol Endocrinol. 2004;18:2790-804 pubmed
    ..rat, orexins orchestrate divergent actions through their G protein-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R)...
  4. Tsuneki H, Kon K, Ito H, Yamazaki M, Takahara S, Toyooka N, et al. Timed Inhibition of Orexin System by Suvorexant Improved Sleep and Glucose Metabolism in Type 2 Diabetic db/db Mice. Endocrinology. 2016;157:4146-4157 pubmed
    ..Our results provide insight into the development of novel pharmacological interventions for type 2 diabetes that target the orexin-operated sleep/wake regulatory system. ..
  5. Vassalli A, Li S, Tafti M. Comment on "Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2". Sci Transl Med. 2015;7:314le2 pubmed publisher
    ..now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.'s findings. ..
  6. Zhang Z, Li Q, Liu F, Sun Y, Zhang J. Prevention of diet-induced obesity by safflower oil: insights at the levels of PPARalpha, orexin, and ghrelin gene expression of adipocytes in mice. Acta Biochim Biophys Sin (Shanghai). 2010;42:202-8 pubmed
    ..So, the SAF diet can alter adipocytic adiposity-related gene expression and result in effective amelioration of diet-induced obesity. ..
  7. Kalogiannis M, Hsu E, Willie J, Chemelli R, Kisanuki Y, Yanagisawa M, et al. Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS ONE. 2011;6:e18697 pubmed publisher
    ..Since perturbations of muscarinic transmission altered arrest frequency but not lifetime, our findings suggest cholinergic systems influence arrest initiation without influencing circuits that determine arrest duration. ..
  8. Irukayama Tomobe Y, Ogawa Y, Tominaga H, Ishikawa Y, Hosokawa N, Ambai S, et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114:5731-5736 pubmed publisher
    ..We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185...
  9. Hasegawa E, Maejima T, Yoshida T, Masseck O, Herlitze S, Yoshioka M, et al. Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity. Proc Natl Acad Sci U S A. 2017;114:E3526-E3535 pubmed publisher
    ..Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing. ..

More Information


  1. Ishibashi M, Gumenchuk I, Miyazaki K, Inoue T, Ross W, Leonard C. Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization. J Neurosci. 2016;36:10097-115 pubmed publisher
  2. Fatemi I, Shamsizadeh A, Roohbakhsh A, Ayoobi F, Sanati M, Motevalian M. Increase in mRNA Level of Orexin1 and 2 Receptors Following Induction of Experimental Autoimmune Encephalomyelitis in Mice. Iran J Allergy Asthma Immunol. 2016;15:20-6 pubmed
    ..Then, the expression profiles of prepro-orexin, orexin 1 receptors (OX1R) and orexin 2 receptors (OX2R) in hypothalamic region were assessed using real-time PCR method...
  3. Hasegawa E, Yanagisawa M, Sakurai T, Mieda M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest. 2014;124:604-16 pubmed publisher
    ..These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy. ..
  4. Wang C, Pan Y, Zhang R, Bai B, Chen J, Randeva H. Heterodimerization of mouse orexin type 2 receptor variants and the effects on signal transduction. Biochim Biophys Acta. 2014;1843:652-63 pubmed
    ..The nature of this signaling pathway has significant implications for the role of Orexin in the regulation of physiological processes including the homeostasis of feeding. ..
  5. Duguay D, Bélanger Nelson E, Mongrain V, Beben A, Khatchadourian A, Cermakian N. Dynein light chain Tctex-type 1 modulates orexin signaling through its interaction with orexin 1 receptor. PLoS ONE. 2011;6:e26430 pubmed publisher
    ..in the regulation of the sleep-wake cycle, feeding and reward, via activation of orexin receptors 1 and 2 (OX1R, OX2R). The loss of orexin peptides or functional OX2R has been shown to cause the sleep disorder, narcolepsy...
  6. Chen J, Karteris E, Collins D, Randeva H. Differential expression of mouse orexin receptor type-2 (OX2R) variants in the mouse brain. Brain Res. 2006;1103:20-4 pubmed
    We have identified two novel mouse orexin type-2 receptor (OX2R) splice variants: OX2alphaR and OX2betaR. Here, we have mapped in detail the differential gene expression of OX2alphaR and OX2betaR in the mouse brain...
  7. Funato H, Tsai A, Willie J, Kisanuki Y, Williams S, Sakurai T, et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. 2009;9:64-76 pubmed publisher
    ..Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype...
  8. Mochizuki T, Arrigoni E, Marcus J, Clark E, Yamamoto M, Honer M, et al. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci U S A. 2011;108:4471-6 pubmed publisher
    ..narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase...
  9. Hondo M, Nagai K, Ohno K, Kisanuki Y, Willie J, Watanabe T, et al. Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states. Acta Physiol (Oxf). 2010;198:287-94 pubmed publisher
    ..Downstream pathways of OX(2)R other than the histaminergic system might play an important role in the maintenance of sleep/wake states. ..
  10. Hungs M, Mignot E. Hypocretin/orexin, sleep and narcolepsy. Bioessays. 2001;23:397-408 pubmed
    ..Two known receptors, Hcrtr1 and Hcrtr2, have been reported...
  11. Terao A, Apte Deshpande A, Morairty S, Freund Y, Kilduff T. Age-related decline in hypocretin (orexin) receptor 2 messenger RNA levels in the mouse brain. Neurosci Lett. 2002;332:190-4 pubmed
    ..messenger RNA (mRNA) levels of preprohcrt in the hypothalamus, and hcrt receptor 1 (hcrtr1) and hcrt receptor 2 (hcrtr2) in eight brain regions of 3, 12, 18 and 24 months old C57BL/6 mice...
  12. Mishima K, Fujiki N, Yoshida Y, Sakurai T, Honda M, Mignot E, et al. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep. 2008;31:1119-26 pubmed
    To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy. Animal and human study...
  13. Lee H, Chang L, Ho Y, Teng S, Hwang L, Mackie K, et al. Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray. Neuropharmacology. 2016;105:577-586 pubmed publisher
    ..Although activating either OX1 or OX2 receptors in the vlPAG can lead to antinociception, only OX1 receptor-initiated antinociception is endocannabinoid-dependent. ..
  14. PEREZ M, Pavlovic A, Shang C, Wheeler M, Miller C, Liu J, et al. Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure. J Am Coll Cardiol. 2015;66:2522-33 pubmed publisher
    ..Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3...
  15. Wei W, Motoike T, Krzeszinski J, Jin Z, Xie X, Dechow P, et al. Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action. Cell Metab. 2014;19:927-40 pubmed publisher
    ..Here, we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation...
  16. Arendt D, Hassell J, Li H, Achua J, Guarnieri D, DiLeone R, et al. Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinology. 2014;40:17-26 pubmed publisher
    ..Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders. ..
  17. Soya S, Shoji H, Hasegawa E, Hondo M, Miyakawa T, Yanagisawa M, et al. Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation. J Neurosci. 2013;33:14549-57 pubmed publisher
    ..In contrast, Ox2r(-/-) mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing ..
  18. Ortega J, Katner J, Davis R, Wade M, Nisenbaum L, Nomikos G, et al. Modulation of neurotransmitter release in orexin/hypocretin-2 receptor knockout mice: a microdialysis study. J Neurosci Res. 2012;90:588-96 pubmed publisher
    ..In the PFC, the evoked release of the monoamines NE, 5-HT, and DA seems to be controlled negatively by OX2 receptors. ..
  19. Willie J, Chemelli R, Sinton C, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci. 2001;24:429-58 pubmed
  20. Mieda M, Hasegawa E, Kisanuki Y, Sinton C, Yanagisawa M, Sakurai T. Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci. 2011;31:6518-26 pubmed publisher
    ..Thus, each orexin receptor subtype plays differential roles in gating NREM and REM sleep through distinct neuronal pathways. ..
  21. Malherbe P, Borroni E, Gobbi L, Knust H, Nettekoven M, Pinard E, et al. Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol. 2009;156:1326-41 pubmed publisher
    ..EMPA did not impair performance of rats in the rotarod procedure. EMPA is a high-affinity, reversible and selective OX(2) receptor antagonist, active in vivo, which should prove useful for analysis of OX(2) receptor function. ..
  22. Guo Y, Feng P. OX2R activation induces PKC-mediated ERK and CREB phosphorylation. Exp Cell Res. 2012;318:2004-13 pubmed publisher
    ..In this study, we report the effects of orexin 2 receptor (OX2R) activation on cell signaling in CHO cells over-expressing OX2R and in mouse hypothalamus cell line CLU172...
  23. Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M. Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci. 2010;30:12642-52 pubmed publisher
    ..Here, we revealed that orexin neurons are directly and indirectly activated by orexin via the orexin 2 receptor (OX2R)...
  24. Sellayah D, Bharaj P, Sikder D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab. 2011;14:478-90 pubmed publisher
    ..Thus, orexin plays an integral role in adaptive thermogenesis and body weight regulation via effects on BAT differentiation and function. ..
  25. Kozlov S, Bogenpohl J, Howell M, Wevrick R, Panda S, Hogenesch J, et al. The imprinted gene Magel2 regulates normal circadian output. Nat Genet. 2007;39:1266-72 pubmed
  26. Scott M, Marcus J, Pettersen A, Birnbaum S, Mochizuki T, Scammell T, et al. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res. 2011;222:289-94 pubmed publisher
    ..No difference in anxiety-like behavior was noted following hcrtr1 deletion. In contrast, hcrtr2-null mice displayed an increase in behavioral despair with no effect on measures of anxiety...