Lipid signaling cascades of orexin/hypocretin receptors

Orexins - orexin-A and orexin-B - are neuropeptides with significant role in regulation of fundamental physiological processes such as sleep-wakefulness cycle. Orexins act via G-protein-coupled OX1 and OX2 receptors, which are found, in addition to the central nervous system, also in a number of peripheral organs. Orexin receptors show high degree of signaling promiscuity. One particularly prominent way of signaling for these receptors is via phospholipase cascades, including the phospholipase C, phospholipase D and phospholipase A2 cascades, and also diacylglycerol lipase and phosphoinositide-3-kinase pathways. Most analyses have been performed in recombinant cells; there are indications of some of these cascades in native cells while the significance of other cascades remains to be shown. In this review, I present these pathways, their activation mechanisms and their physiological significance.