OX1R

OX1R, or orexin receptor 1, is a G protein-coupled receptor that binds the neuropeptides orexin A and orexin B, produced by neurons in the lateral hypothalamus. In humans it is encoded by the HCRTR1 gene. OX1R is expressed in several brain regions, including the locus coeruleus, tuberomammillary nucleus, ventral tegmental area, and other areas associated with arousal and homeostatic regulation.

OX1R signaling is primarily coupled to Gq/11 proteins. Activation of the receptor stimulates phospholipase C, leading to inositol triphosphate and diacylglycerol production, mobilization of intracellular calcium, and changes in neuronal excitability. Orexin A and orexin B bind with differing affinities, with orexin A often showing substantial activity at OX1R. Through these signaling pathways, OX1R contributes to the modulation of wakefulness, arousal, reward processing, feeding, and energy balance.

Physiologically, OX1R participates in promoting wakefulness and stabilizing arousal, as well as modulating motivational and reward circuits, stress responses, and metabolic regulation. Orexin signaling is a key component of the sleep-wake system, and disruption of orexin signaling is linked to narcolepsy and related disorders. The receptor operates in concert with OX2R to regulate these processes.

Pharmacologically, selective antagonists of OX1R, such as SB-334867, have been used in animal studies to examine roles in drug seeking and appetite. Dual orexin receptor antagonists that block both OX1R and OX2R have been developed for treating insomnia. Selective OX1R antagonists are under investigation for potential applications in addiction, anxiety, and metabolic disorders, but none are currently approved for clinical use.