preproorexinorexin

Preproorexin, also called prepro-orexin, is the hypothalamic neuropeptide precursor that gives rise to the orexin (hypocretin) peptides. It is encoded by the HCRT gene and is synthesized as a relatively small precursor protein that includes a signal peptide for secretion and a central pro-orexin region that will be processed into active peptides.

During post-translational processing, prohormone convertases and other peptidases cleave preproorexin to generate the mature neuropeptides orexin-A and orexin-B. The peptides typically undergo N-terminal pyroglutamylation and other processing steps before being released from orexin neurons in the hypothalamus.

Orexin peptides exert their effects via two G protein-coupled receptors, OX1R and OX2R, and project broadly to many brain regions. They regulate arousal and wakefulness, feeding and energy balance, reward, stress responses, and autonomic functions. Activity of the orexin system promotes wakefulness and inhibits sleep.

Clinical relevance: In humans, degeneration of orexin-producing neurons leads to narcolepsy type 1, characterized by excessive daytime sleepiness and cataplexy. Pharmacologically, orexin receptor antagonists (for example, suvorexant and lemborexant) are used to treat insomnia by dampening orexin signaling.

Evolution and research: The preproorexin/HCRT system is conserved among vertebrates and is a focus of sleep-wake regulation research, with ongoing studies examining its roles in metabolism, addiction, and stress responses.