Hypocretin (orexin) receptor 1

Hypocretin (orexin) receptor 1 (also known as HCRTR1, OX1R, OX1 receptor, or OX1R) is a G protein-coupled receptor (GPCR) that binds the neuropeptides hypocretin-1 (orexin A) and hypocretin-2 (orexin B) with higher affinity than hypocretin receptor 2. It is primarily coupled to Gq proteins, leading to activation of phospholipase C and subsequent increases in intracellular calcium levels.

The hypocretin system, comprising the hypocretin peptides and their receptors, plays a critical role in regulating sleep-wake states, arousal, appetite, and reward-seeking behaviors. HCRTR1 is predominantly expressed in specific brain regions including the locus coeruleus, dorsal raphe nucleus, and tuberomammillary nucleus, key areas involved in arousal and wakefulness.

Activation of HCRTR1 promotes wakefulness and suppresses REM sleep. Dysfunction of the hypocretin system, including decreased levels of hypocretin peptides or impaired receptor signaling, is implicated in the pathophysiology of narcolepsy, a neurological disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations.

Selective HCRTR1 antagonists are being developed and used clinically as treatments for insomnia. These antagonists promote sleep by blocking the wake-promoting effects of hypocretin signaling. Research continues to investigate the role of HCRTR1 in other physiological and pathological processes, including addiction, anxiety, and metabolic disorders.