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 [5,20]. 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 [20]. 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 [15], and orexin neuron loss is associated with the human disorder [17-18]. 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 [2-3,8]. Small molecule orexin receptor antagonists have been shown to increase sleep across species, including man [4,21]. In 2014, suvorexant was the first orexin receptor antagonist approved for the treatment of insomnia [7].


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 [20]). 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 [12-14,20]. 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 [1,9-11,19,22].


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 [6,16,23,25] . Both orexin-A and -B have nearly equal affinity for OX2 receptors (IC50s of 38 and 36 nM, respectively [20]), and elevate intracellular calcium levels through activation of Gq and phospholipase C activity, but the receptors are also capable of activating Gs, Gi, and potentially ion channels [12-14,20]. OX2 receptors predominantly mediate the control of arousal induced by orexin neuropeptides, based on results from dog and rodents [15,21,24].


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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]

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