Orexin receptors: Introduction


The orexins (orexin-A and orexin-B, also known as hypocretin-1 and hypocretin-2) are neuropeptides derived from a single precursor expressed in the posterior lateral and medial hypothalamus. These peptides were discovered independently by two different groups [5,19]. The name orexin (after orexis, Greek for appetite) was derived from experiments showing increased food intake after daytime intracerebral administration of the peptides in nocturnal rodents [19]. The name hypocretin reflects their hypothalamic expression and sequence similarity to the incretin peptide family [5]. While their effect on appetite is still controversial, and may be the result of increased arousal, orexins have a prominent role in promoting wakefulness and stabilizing vigilance state as demonstrated by pharmacological or genetic modulation of the orexin receptor signalling. Mutations in the OX2 receptor are responsible for canine narcolepsy [13], and orexin neuron loss is associated with the human disorder [15-16]. Targeted mutagenesis of the gene encoding the orexin ligands, or genetically induced postnatal destruction of orexin-producing neurons in rodents results in a salient narcoleptic phenotype [2-3,7]. Small molecule orexin receptor antagonists have been shown to increase sleep across species, including man [4]. In 2014, suvorexant was the first orexin receptor antagonist approved for the treatment of insomnia [6]


OX1 receptors are G protein-coupled receptors whose orthologs are present throughout mammals [25]. In mammals, CNS expression includes brainstem nuclei involved in arousal and sleep/wake regulation as well as nuclei involved in reward signaling. Orexin-A and -B neuropeptides have different affinities for OX1 receptors (IC50s of 20 and 420 nM, respectively [19]). Receptor activation results in elevated intracellular calcium levels mediated by Gq and phospholipase C activation, but contributions from Gs- and Gi-mediated regulation of cAMP levels as well as non-selective cation channels have also been described [9,12,20,23]. OX1 receptor signaling in sleep/wake regulation is not as well defined as for OX2 receptors, but has been implicated in mood, anxiety, memory and reward, with mixed effects on feeding reported [1,8,10,18,21].


OX2 receptors are found throughout vertebrates and, like OX1 receptors, are expressed in brainstem and striatal nuclei, with additional expression in arousal-promoting histaminergic nuclei [14,22,25]. Both orexin-A and -B have nearly equal affinity for OX2 receptors (IC50s of 38 and 36 nM, respectively [19]), and stimulate intracellular calcium levels through OX2-mediated induction of Gq and phospholipase C activity, but are also capable of activating Gs, Gi, and potentially ion channels [9,11,17,20]. OX2 receptors predominantly mediate the control of arousal induced by orexin neuropeptides, based on results from dog and rodents [4,13,24].


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1. Abbas MG, Shoji H, Soya S, Hondo M, Miyakawa T, Sakurai T. (2015) Comprehensive Behavioral Analysis of Male Ox1r (-/-) Mice Showed Implication of Orexin Receptor-1 in Mood, Anxiety, and Social Behavior. Front Behav Neurosci, 9: 324. [PMID:26696848]

2. Beuckmann CT, Sinton CM, Williams SC, Richardson JA, Hammer RE, Sakurai T, Yanagisawa M. (2004) Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J. Neurosci., 24 (18): 4469-77. [PMID:15128861]

3. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y et al.. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98 (4): 437-51. [PMID:10481909]

4. Chow M, Cao M. (2016) The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nat Sci Sleep, 8: 81-6. [PMID:27051324]

5. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS et al.. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A., 95 (1): 322-7. [PMID:9419374]

6. FDA. FDA approves new type of sleep drug, Belsomra. Accessed on 05/09/2016. Modified on 05/09/2016. FDA.gov, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm

7. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M et al.. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 30 (2): 345-54. [PMID:11394998]

8. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR. (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul. Pept., 96 (1-2): 45-51. [PMID:11102651]

9. Holmqvist T, Akerman KE, Kukkonen JP. (2002) Orexin signaling in recombinant neuron-like cells. FEBS Lett., 526 (1-3): 11-4. [PMID:12208495]

10. Johnson PL, Federici LM, Fitz SD, Renger JJ, Shireman B, Winrow CJ, Bonaventure P, Shekhar A. (2015) OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES. Depress Anxiety, 32 (9): 671-83. [PMID:26332431]

11. Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW. (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. [PMID:11549701]

12. Kukkonen JP, Åkerman KEO. (2005) Intracellular Signal Pathways Utilized by the Hypocretin/Orexin Receptors. In Hypocretins. Integrators of Physiological Signals Edited by de Lecea L, Sutcliffe JG (Verlag: Springer) 221-231. [ISBN:9780387254463]

13. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98 (3): 365-76. [PMID:10458611]

14. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol., 435 (1): 6-25. [PMID:11370008]

15. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet, 355 (9197): 39-40. [PMID:10615891]

16. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R 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. [PMID:10973318]

17. 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. [PMID:11600545]

18. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE. (2001) SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur. J. Neurosci., 13 (7): 1444-52. [PMID:11298806]

19. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S et al.. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92 (4): 573-85. [PMID:9491897]

20. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F. (1999) Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br. J. Pharmacol., 128 (1): 1-3. [PMID:10498827]

21. Steiner MA, Sciarretta C, Pasquali A, Jenck F. (2013) The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome. Front Pharmacol, 4: 165. [PMID:24416020]

22. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett, 438: 71-75. [PMID:9821961]

23. Turunen PM, Ekholm ME, Somerharju P, Kukkonen JP. (2010) Arachidonic acid release mediated by OX1 orexin receptors. Br. J. Pharmacol., 159 (1): 212-21. [PMID:20002100]

24. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA et al.. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron, 38 (5): 715-30. [PMID:12797957]

25. Wong KK, Ng SY, Lee LT, Ng HK, Chow BK. (2011) Orexins and their receptors from fish to mammals: a comparative approach. Gen. Comp. Endocrinol., 171 (2): 124-30. [PMID:21216246]

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