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 [6,23]. 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 [23]. The name hypocretin reflects their hypothalamic expression and sequence similarity to the incretin peptide family [6]. Orexins act on two receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions and disturbances that include sleep-arousal, feeding-metabolism, reward-addiction, fear, anxiety, depression, pain gating and cognition [13].
Orexin receptors are G protein-coupled receptors whose orthologs are present throughout mammals [28]. 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 [16-18,23]. Orexins have a prominent role in promoting wakefulness and stabilizing vigilance state as demonstrated by pharmacological or genetic modulation of the orexin receptor signalling. Loss-of-function mutations in the OX2 receptor are responsible for canine narcolepsy [19], and orexin neuron loss is associated with the human disorder [21-22]. 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 [2,4,10]. Small molecule orexin receptor antagonists (non-selective or OX2-selective) have been shown to increase sleep across species, including man [5,24]. In 2014 suvorexant was the first orexin receptor antagonist approved for the treatment of insomnia [9], later followed by lemborexant and daridorexant.

In mammals, CNS expression includes brainstem nuclei involved in arousal and sleep/wake regulation as well as nuclei involved in reward signaling [20,26]. Orexin-A and -B neuropeptides have different affinities for OX1 receptors (IC50s of 20 and 420 nM, respectively [23]). OX1 receptor signaling in sleep/wake regulation is not as well defined as for OX2 receptors, but has been particularly implicated in reward and addiction, with mixed effects on feeding reported [1,11,14-15,25,29].

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 [7,20,26]. Both orexin-A and -B have nearly equal affinity for OX2 receptors (IC50s of 38 and 36 nM, respectively [23]). Based on results from dog, rodents and human, OX2 receptors are predominantly responsible for the control of arousal and vigilance state stabilization mediated by orexin neuropeptides, and thus exogenous activation of OX2 receptors increases wakefulness and reduces cataplexy in narcolepsy [3,8,12,19,24,27,29].


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27. 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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29. Yamamoto H, Nagumo Y, Ishikawa Y, Irukayama-Tomobe Y, Namekawa Y, Nemoto T, Tanaka H, Takahashi G, Tokuda A, Saitoh T et al.. (2022) OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy. PLoS One, 17 (7): e0271901. [PMID:35867683]

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