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Lipid signaling cascades of orexin/hypocretin receptors

Jyrki P Kukkonen1

  • 1Biochemistry and Cell Biology, Department of Veterinary Biosciences, POB 66, FIN-00014, University of Helsinki, Finland.

Biochimie
|July 2, 2013
PubMed

Insights

Orexins (orexin-A and orexin-B) are neuropeptides regulating sleep. Their receptors activate various signaling pathways, including phospholipase cascades, with roles in both the brain and peripheral organs.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Physiology

Background:

  • Orexins, including orexin-A and orexin-B, are crucial neuropeptides involved in regulating fundamental physiological processes, notably the sleep-wakefulness cycle.
  • These neuropeptides exert their functions through G-protein-coupled OX1 and OX2 receptors, which are present in the central nervous system and various peripheral organs.

Purpose of the Study:

  • To review the signaling pathways activated by orexin receptors.
  • To elucidate the activation mechanisms and physiological significance of these pathways.

Main Methods:

  • Review of existing literature on orexin receptor signaling.
  • Analysis of phospholipase cascades (PLC, PLD, PLA2), diacylglycerol lipase, and PI3K pathways.
  • Comparison of findings from recombinant and native cell studies.

Main Results:

  • Orexin receptors exhibit significant signaling promiscuity, activating multiple downstream pathways.
  • Prominent signaling involves phospholipase cascades (C, D, A2) and diacylglycerol lipase and phosphoinositide-3-kinase pathways.
  • While some pathways are confirmed in native cells, the significance of others requires further investigation.

Conclusions:

  • Orexin receptor signaling is complex, involving diverse phospholipase cascades and lipid kinase pathways.
  • Understanding these pathways is essential for comprehending orexin's physiological roles in the CNS and periphery.
  • Further research is needed to fully establish the significance of all identified cascades in native cellular contexts.
Keywords:
2-AG2-arachidonoylglycerolAACNSDAGDAG lipaseDAGLDOGERKEndocannabinoidG-protein-coupled receptorGPCRGPLHypocretinIP(3)Ion fluxesKB-R7943MAFPN-acyl-phosphatidylethanolamineN-arachidonoylethanolamineNAPENSCCOX(1)OX(2)OrexinPAPCPC-PLCPC-specific PLCPDK1PIPI3KPIPPIP(2)PIP(3)PIsPKB, PKC and PKDPLA(1), PLA(2), PLB, PLC and PLDPhospholipaseTRP (channel)U73122a NCX inhibitora PLC inhibitora cPLA(2)α/ζ inhibitoranandamidearachidonic acidcPLA(2) and iPLA(2)central nervous systemcytosolic (Ca(2+)-dependent) and intracellular (Ca(2+)-independent) PLA(2), respectivelydiacylglyceroldioctanoylglycerolextracellular signal-regulated kinaseglycerophospholipidinositol-1,4,5-trisphosphatelyso(glycero)phospholipidlysoGPLlysoPAlysophosphatidic acidmethyl arachidonyl fluorophosphonatenon-selective cation channelorexin 1 receptororexin 2 receptorphosphatidic acidphosphatidylcholinephosphatidylinositolphosphatidylinositol-3,4,5-trisphosphatephosphatidylinositol-4,5-bisphosphatephosphatidylinositolmonophosphatephosphatidylinositols (including differentially phosphorylated species PI, PIP, PIP(2) and PIP(3))phosphoinositide-3-kinasephosphoinositide-dependent kinase 1phospholipase A(1), A(2), B, C and D, respectivelyprotein kinase B, C and D, respectivelypyrrophenonetransient receptor potential (channel)

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