Orexin (hypocretin) peptides and their two known G-protein-coupled receptors play essential roles in sleep-wake control and powerfully influence other systems regulating appetite/metabolism, stress and reward. Consequently, drugs that influence signalling by these receptors may provide novel therapeutic opportunities for treating sleep disorders, obesity and addiction. It is therefore critical to understand how these receptors operate, the nature of the signalling cascades they engage, and their physiological targets. In this review, we evaluate what is currently known about orexin receptor signalling cascades while a sister review (Leonard & Kukkonen, this issue) focuses on tissue-specific responses. The evidence suggests that orexin receptor signalling is multi-faceted and substantially more diverse than originally thought. Indeed, orexin receptors are able to couple to members of at least three G-protein families and possibly other proteins, through which they regulate non-selective cation channels, phospholipases, adenylyl cyclase, and protein and lipid kinases. In the central nervous system, orexin receptors produce neuroexcitation by post-synaptic depolarisation via activation of non-selective cation channels, inhibition of K⁺ channels and activation of Na⁺ /Ca²⁺ -exchange, but also can stimulate the release of neurotransmitters by presynaptic actions and modulate synaptic plasticity. Ca²⁺ signalling is also prominently influenced by these receptors, both via the classical phospholipase C-Ca²⁺ release pathway but also via Ca²⁺ influx, mediated by several pathways. Upon longer-lasting stimulation, plastic effects are seen in some cell types while others, especially cancer cells, are stimulated to die. Thus, orexin receptor signals appear highly tuneable depending on the milieu in which they are operating.
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PMID:

 

23902572

 

[PubMed – as supplied by publisher]