HCRTR1

HCRTR1, or hypocretin receptor 1, also known as orexin receptor type 1 (OX1R), is a G protein-coupled receptor that binds the neuropeptides orexin-A and orexin-B, produced by hypothalamic neurons. It is a member of the orexin receptor family and participates in signaling pathways that regulate arousal, wakefulness, energy homeostasis, and feeding behaviors.

Signal transduction through HCRTR1 primarily involves Gq/11 proteins, leading to activation of phospholipase C, production of inositol trisphosphate and diacylglycerol, and an increase in intracellular calcium. In certain cell types, the receptor can couple to other G proteins and influence cAMP signaling, indicating context-dependent signaling.

HCRTR1 is expressed in multiple brain regions including areas involved in arousal and autonomic regulation, such as parts of the cortex, hypothalamus, and brainstem. Through orexin signaling, HCRTR1 contributes to the promotion of wakefulness and alertness, while also participating in metabolic signaling and modulatory effects on reward circuits. The receptor often functions in concert with HCRTR2 (OX2R) to regulate sleep-wake states.

Pharmacology and clinical relevance: Selective antagonists for HCRTR1, such as SB-334867, are used in research to dissect the receptor’s role in sleep and arousal. Clinically, dual orexin receptor antagonists like suvorexant and lemborexant block both OX1R and OX2R to treat insomnia by reducing orexin-driven arousal. Variants in the HCRTR1 gene have been studied for associations with sleep traits and metabolic phenotypes, but findings are not consistently replicated; disruption of orexin signaling, including OX1R activity, contributes to the narcolepsy phenotype via loss of orexin neuron signaling.

See also: Orexin, HCRTR2, Suvorexant.