preprohypocretin

Preprohypocretin, also known as prepro-orexin, is the precursor protein from which the orexin neuropeptides are derived. In mammals, it is encoded by the HCRT gene and produced by neurons in the lateral hypothalamus. The initial translation product contains an N-terminal signal peptide that directs it to the secretory pathway; after the signal peptide is removed, the remaining propeptide is processed proteolytically to generate the mature orexin peptides orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Processing is carried out by endoproteases such as prohormone convertases and other peptidases, followed by carboxypeptidases that trim peptide ends.

The mature orexin peptides are secreted and act on two G-protein-coupled receptors, OX1R and OX2R, to regulate arousal and wakefulness, feeding and energy homeostasis, and reward and stress responses. Orexin signaling is particularly important for maintaining wakefulness; disruption of orexin production or signaling is linked to narcolepsy in humans and other mammals, often with cataplexy and disrupted sleep–wake patterns.

In comparative biology, preprohypocretin sequences are conserved across vertebrates, though there is variation among species in exact sequence and peptide processing. The propeptide's layout funneling into two distinct mature peptides reflects the general strategy of neuropeptide production in the hypothalamus.

Research on preprohypocretin and orexin pathways continues to inform understanding of sleep disorders and energy balance, and it has implications for potential therapies targeting orexin receptors.