Hypocretin receptor (HCRTR)

Hypocretin neurons, located primarily in the lateral hypothalamus, are the exclusive source of the wake-promoting neuropeptides hypocretin-1 and hypocretin-2, also known as orexin-A and orexin-B [10, 16]. These neurons project widely throughout the brain to regulate arousal, energy homeostasis, and reward-seeking behavior by activating two G protein-coupled receptors, hypocretin receptor type 1 and hypocretin receptor type 2 [1, 21]. The pathological loss of approximately 90% of these neurons is the definitive cause of narcolepsy type 1, which is characterized by a severe deficiency of hypocretin in the cerebrospinal fluid [10, 14]. Conversely, overactive hypocretin signaling is associated with insomnia, making the receptors a major therapeutic target in sleep medicine [2, 15]. Dual orexin receptor antagonists (DORAs), such as suvorexant and daridorexant, are clinically approved for the treatment of insomnia by inhibiting wake-promoting pathways [5, 18]. Furthermore, selective hypocretin receptor agonists are currently in clinical development as potentially transformative therapies for narcolepsy to compensate for the loss of endogenous hypocretin signaling [11, 21].

Other names

Orexin receptorHCRTR1HCRTR2OX1ROX2RHypocretin receptor type 1Hypocretin receptor type 2Orexin/hypocretin receptor

Dual orexin receptor antagonism for the treatment of insomnia; selective orexin receptor type 2 agonism for the treatment of narcolepsy; and selective orexin receptor type 2 antagonism for mood disorders.