Orexin/Hypocretin Signaling

  • Jyrki P. KukkonenEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)


Orexin/hypocretin peptide (orexin-A and orexin-B) signaling is believed to take place via the two G-protein-coupled receptors (GPCRs), named OX1 and OX2 orexin receptors, as described in the previous chapters. Signaling of orexin peptides has been investigated in diverse endogenously orexin receptor-expressing cells – mainly neurons but also other types of cells – and in recombinant cells expressing the receptors in a heterologous manner. Findings in the different systems are partially convergent but also indicate cellular background-specific signaling. The general picture suggests an inherently high degree of diversity in orexin receptor signaling.

In the current chapter, I present orexin signaling on the cellular and molecular levels. Discussion of the connection to (potential) physiological orexin responses is only brief since these are in focus of other chapters in this book. The same goes for the post-synaptic signaling mechanisms, which are dealt with in Burdakov: Postsynaptic actions of orexin. The current chapter is organized according to the tissue type, starting from the central nervous system. Finally, receptor signaling pathways are discussed across tissues, cell types, and even species.


Adenylyl cyclase Calcium Diacylglycerol lipase Endocannabinoid Gi Gq Gs Heterotrimeric G-protein Hypocretin K+ channel Na+/Ca2+-exchanger Non-selective cation channel Orexin OX1 receptor OX2 receptor Phospholipase A2 Phospholipase C Phospholipase D Protein kinase C 



2-Arachidonoyl glycerol


Sigma 1 receptor


κ Opioid receptor


Adenylyl cyclase


Adrenocorticotropic hormone


Bioluminescence and fluorescence/Förster resonance energy transfer, respectively


Chinese hamster ovary (cells)


Central nervous system

CRF and CRF1

Corticotropin-releasing factor and corticotropin-releasing factor receptor 1, respectively




Endoplasmic reticulum


Guanine nucleotide exchange factor


G-protein-coupled receptor

Gαβγ, Gα and Gβγ

Heterotrimeric G-protein heterotrimeric complex, α-subunit, and the βγ-subunit complex, respectively




c-Jun N-terminal kinase


Mitogen-activated protein kinase


Mouse embryonic fibroblast


Mammalian target of rapamycin complex 1




Non-selective cation channel


p70 ribosomal S6 kinase


p90 ribosomal S6 kinase






Protein kinase A, B, and C, respectively

PLA2, PLC, and PLD

Phospholipase A2, C, and D, respectively


Protein phosphatase 5


Transient receptor potential (channel)


Ventral tegmental area


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Authors and Affiliations

  1. 1.Biochemistry and Cell Biology, Department of Veterinary BiosciencesUniversity of HelsinkiHelsinkiFinland

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