Orexins are neuropeptides synthesized by hypothalamic neurons that project throughout the brain. They regulate sleep, wakefulness, breathing, reward system and drug addiction. They strongly impact on sleep-wakefulness since orexin deficiency results in narcolepsy and cataplexy. Functions of orexins have been also described in a few peripheral tissues. The actions of orexins are mediated by two G protein-coupled receptors (GPCR) OX1R and OX2R. Classically, activation of OXRs induces cellular calcium transients through coupling to Gq proteins. An unexpected and fascinating aspect of orexins has recently emerged when we showed that orexins induce dramatic apoptosis in colon cancer cells. I will present recent data related to the apoptotic actions of orexins and the entirely novel mechanism whereby OX1R (and probably OX2R) triggers apoptosis. Orexins induce tyrosine phosphorylation of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in OX1R. These motifs were previously considered as hallmarks of immunoreceptors. The phosphorylation of ITIMs results in recruitment and activation of tyrosine phosphatase SHP-2 and cytochrome c-mediated mitochondrial apoptosis. This mechanism is independent of Gαq-mediated activation of phospholipase C but dependent on Src stimulation by Gβγ upon OX1R activation. Finally, I will speculate on: 1) the potential importance of ITIMs in the large family of GPCRs. We show that ITIMcontaining proteins represent roughly 1% of all genomes but up to 85% of human GPCRs. ITIMs are well conserved during phylogenesis and their possible role in GPCR function will be discussed; 2) the reason why adult brain neurons which express orexin receptors and are stimulated by endogenous orexins do not undergo devastating apoptosis. Since aberrant neuronal death is an outstanding feature of neurodegenerative diseases and mitochondrial death-route is important during brain maturation, the role of orexins in these processes is an open question.
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