Orexin Signaling: A Complex, Multifaceted Process

Abstract

The orexin system comprises two G protein-coupled receptors, OX1 and OX2 receptors (OX1R and OX2R, respectively), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). For the receptors, a complex array of signaling behaviors has been reported. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system’s function in vivo in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.

What evidence is there for implicating the brain orexin system in neuropsychiatric symptoms in dementia?

“…Rodent studies indicate that the orexin system plays a role in the regulation of reward processing (7,45,46). OX neurons project to and modulate the activity of brain areas involved in reward-related behaviors including those of the mesocorticolimbic pathway and the brain's "hedonic hotspots" (8,47).…”

“…The orexin system comprises orexin (OX)-producing neurons that are located in a specific area of the dorso-lateral hypothalamus. OX neurons synthetize the peptide prepro-orexin, which is then cleaved to produce the two orexin peptides OX-A and OX-B (also named hypocretin-1 and hypocretin-2) (7). Axons of OX neurons project to a wide range of brain regions where OX-A and OX-B are then released (8) and bind to OX1 and OX2 receptors (OX1R, OX2R) to affect neuronal signaling (7).…”

“…OX neurons synthetize the peptide prepro-orexin, which is then cleaved to produce the two orexin peptides OX-A and OX-B (also named hypocretin-1 and hypocretin-2) (7). Axons of OX neurons project to a wide range of brain regions where OX-A and OX-B are then released (8) and bind to OX1 and OX2 receptors (OX1R, OX2R) to affect neuronal signaling (7). As such, the OX system modulates several homeostatic functions and behaviors.…”

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“…3 The interaction of orexins with their receptors predominantly activates G q/11 , G s and G i/o proteins, though there is evidence of β-arrestin recruitment as well, and leads to the activation of different downstream signaling pathways, involving effectors such as cAMP, protein kinases, ion channels, and phospholipases. [4][5][6][7][8] In particular, Ca 2+ appears to be a fundamental second messenger for OX-R signaling. Orexin stimulation significantly increases the intracellular levels of Ca 2+ and this effect is predominantly mediated by phospholipase C (PLC).…”

Protective Effects of Orexin A in a Murine Model of Cisplatin-Induced Acute Kidney Injury

“…Orexins also play an important role in the regulation of the neuroendocrine and autonomic nervous systems [ 5 , 6 ]. Orexins act on two G-protein-coupled receptors, orexin receptor type 1 and type 2 [ 7 ]. Orexin receptors are present in the central nervous system (CNS) and many peripheral tissues [ 8 ].…”