Kukkonen, J.P.; Turunen, P.M.

Department of Pharmacology and Department of Physiology, Institute of Biomedicine, Faculty of Medicine, University of Helsinki, Helsinki, Finland

© 2021 The Author(s)
Published by S. Karger AG, Basel

Orexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal pathways are selected and orchestrated is largely unknown. We also have an insufficient understanding of the kind of signaling that is important for specific types of cellular responses. OXRs are able to form complexes with several other G-proteincoupled receptors in vitro, and one possibility is that the complexing partners regulate the use of certain signal transducers. In the central nervous system neurons, the main acute downstream responses of OXR activation are the inhibition of K+ channels and the activation of the Na+/Ca2+ exchanger and nonselective cation channels of unknown identity. The exact nature of the intracellular signal chain between the OXRs and these downstream targets is yet to be elucidated, but the Gq–phospholipase C (PLC) protein kinase C pathway – which is a significant signaling pathway for OXRs in recombinant cells – may be one of the players in neurons. The Gq–PLC pathway may also, under certain circumstances, take the route to diacylglycerol lipase, which leads to the production of the potent endocannabinoid (eCB), 2-arachidonoyl glycerol, and thereby connects orexins with eCB signaling. In addition, OXRs have been studied in the context of neurodegeneration and cancer cell death. Overall, OXR signaling is complex, and it can change depending on the cell type and environment.

• OXR signaling pathways are complex and apparently utilize different signal transducers in different tissues.
• OXRs are capable of making heteromeric complexes with many other GPCRs in recombinant systems, but whether this happens physiologically is largely unknown. However, if it indeed takes place, it might affect OXR signaling, trafficking, and pharmacology.
• OXR signaling can be investigated with appropriate tools: relevant and characterized inhibitors should be used (there are also plenty of new ones) rather than non-selective and toxic ones, which provide us little useful information. Cascades should be measured directly when possible with appropriate positive and negative controls.
• OXRs appear to stimulate 2-AG release in an efficient manner. Thus far, only a few CNS sites have been assessed for this; we would welcome more.

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