Orexin receptors (provisional nomenclature) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor (ENSG00000161610), by proteolytic cleavage [13]. Binding to both receptors may be accomplished with [¹²⁵I]orexin A (human, mouse, rat) [3].

The primary coupling of orexin receptors to G_q/11 proteins is rather speculative and based on the strong activation of phospholipase C. Coupling of both receptors to G_i/o and G_s has also been reported [4,12]; for most cellular responses observed, the G protein pathway is unknown. The rank order of endogenous agonist potency may depend on the cellular signal transduction machinery. The synthetic [Ala¹¹, D-Leu¹⁵]orexin-B may show poor OX₂ receptor selectivity [11].

Loss-of-function mutations in the gene encoding the OX₂ receptor underlie canine hereditary narcolepsy [6].

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1. Asahi, S., Egashira, S., Matsuda, M., Iwaasa, H., Kanatani, A., Ohkubo, M., Ihara, M. and Morishima, H. (2003) Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B. Bioorg Med Chem Lett, 13: 111-113. [PMID:12467628]

2. Hirose, M; Egashira, S; Goto, Y; Hashihayata, T; Ohtake, N; Iwaasa, H; Hata, M; Fukami, T; Kanatani, A; Yamada, K. (2003) N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist. Bioorg. Med. Chem. Lett., 13 (24): 4497-9. [PMID:14643355]

3. Holmqvist, T., Akerman, K. E. and Kukkonen, J. P. (2001) High specificity of human orexin receptors for orexins over neuropeptide Y and other neuropeptides. Neurosci Lett, 305: 177-180. [PMID:11403934]

4. Kukkonen, J.P.; Åkerman, K.E.O. (2005) Hypocretins. Integrators of Physiological Signals. in  Verlag: Springer;. 221-231

5. Langmead, C. J., Jerman, J. C., Brough, S. J., Scott, C., Porter, R. A. and Herdon, H. J. (2004) Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol, 141: 340-346. [PMID:14691055]

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7. Malherbe, P; Borroni, E; Gobbi, L; Knust, H; Nettekoven, M; Pinard, E; Roche, O; Rogers-Evans, M; Wettstein, JG; Moreau, JL. (2009) Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br. J. Pharmacol., 156 (8): 1326-41. [PMID:19751316]

8. Malherbe, P; Borroni, E; Pinard, E; Wettstein, JG; Knoflach, F. (2009) Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: comparison with selective OX1 and OX2 antagonists. Mol. Pharmacol., 76 (3): 618-31. [PMID:19542319]

9. McAtee, L. C., Sutton, S. W., Rudolph, D. A., Li, X., Aluisio, L. E., Phuong, V. K., Dvorak, C. A., Lovenberg, T. W., Carruthers, N. I. and Jones, T. K. (2004) Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists. Bioorg Med Chem Lett, 14: 4225-4229. [PMID:15261275]

10. Porter, R. A., Chan, W. N., Coulton, S., Johns, A., Hadley, M. S., Widdowson, K., Jerman, J. C., Brough, S. J., Coldwell, M., Smart, D., Jewitt, F., Jeffrey, P. and Austin, N. (2001) 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett, 11: 1907-1910. [PMID:11459658]

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12. Ramanjaneya, M; Conner, AC; Chen, J; Kumar, P; Brown, JE; Jöhren, O; Lehnert, H; Stanfield, PR; Randeva, HS. (2009) Orexin-stimulated MAP kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells: diverse roles for orexins A and B. J. Endocrinol., 202 (2): 249-61. [PMID:19460850]

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