orexin1

Orexin receptor type 1, or OX1R, is a G protein-coupled receptor that binds the hypothalamic neuropeptides orexin A and orexin B, with orexin A showing higher affinity. In humans, the receptor is encoded by the HCRTR1 gene. OX1R is part of the orexin/hypocretin signaling system, which originates from neurons in the lateral hypothalamus and projects broadly to multiple brain regions.

OX1R signaling mainly engages Gq/11 proteins, activating phospholipase C, generating inositol trisphosphate and diacylglycerol, and increasing intracellular calcium. The receptor is expressed in several brain areas, including the cortex, amygdala, locus coeruleus, and ventral tegmental area, where it modulates arousal, reward processing, and feeding-related behaviors. Its activity can influence downstream pathways involved in wakefulness and motivation.

Physiologically, orexin signaling promotes wakefulness and arousal and modulates reward and energy balance. Orexin neurons—located in the lateral hypothalamus—provide excitatory input to arousal systems and reward circuits, supporting sustained attention and vigilance. Deficiency of orexin signaling is associated with narcolepsy type 1, reflecting the system’s role in maintaining wakefulness.

Clinically, antagonists that block orexin receptors are used to treat sleep disorders. Dual OX1/OX2 antagonists such as suvorexant and lemborexant are approved for insomnia. Selective OX1R antagonists have been investigated in preclinical studies for addiction and obesity but are not yet approved for clinical use. OX1R continues to be a focus of research for targeted modulation of arousal and motivated behaviors.