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Canna~Fangled Abstracts

Lipid signaling cascades of orexin/hypocretin receptors

By July 6, 2013No Comments
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Review

Lipid signaling cascades of orexin/hypocretin receptors

  • Biochemistry and Cell Biology, Department of Veterinary Biosciences, POB 66, FIN-00014, University of Helsinki, Finland
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  • Highlights
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Orexin receptors show promiscuous signaling.

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Lipid mediators are suggested to be major transducers of orexin responses.

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These are produced mainly by (phospho)lipase cascades.

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Physiological significance of many of the mediators is still unresolved.

 

Abstract

Orexins – orexin-A and orexin-B – are neuropeptides with significant role in regulation of fundamental physiological processes such as sleep-wakefulness cycle. Orexins act via G-protein-coupled OX1 and OX2receptors, which are found, in addition to the central nervous system, also in a number of peripheral organs. Orexin receptors show high degree of signaling promiscuity. One particularly prominent way of signaling for these receptors is via phospholipase cascades, including the phospholipase C, phospholipase D and phospholipase A2 cascades, and also diacylglycerol lipase and phosphoinositide-3-kinase pathways. Most analyses have been performed in recombinant cells; there are indications of some of these cascades in native cells while the significance of other cascades remains to be shown. In this review, I present these pathways, their activation mechanisms and their physiological significance.

Keywords

  • Orexin;
  • Hypocretin;
  • Phospholipase;
  • Endocannabinoid;
  • Ion fluxes

Abbreviations

  • 2-AG, 2-arachidonoylglycerol;
  • AA, arachidonic acid;
  • anandamide, N-arachidonoylethanolamine;
  • CNS,central nervous system;
  • cPLA2 and iPLA2, cytosolic (Ca2+-dependent) and intracellular (Ca2+-independent) PLA2, respectively;
  • DAG, diacylglycerol;
  • DAGL, DAG lipase;
  • DOG, dioctanoylglycerol;
  • ERK,extracellular signal-regulated kinase;
  • GPCR, G-protein-coupled receptor;
  • GPL, glycerophospholipid;
  • IP3,inositol-1,4,5-trisphosphate;
  • KB-R7943, a NCX inhibitor;
  • lysoGPL, lyso(glycero)phospholipid;
  • lysoPA,lysophosphatidic acid;
  • MAFP, methyl arachidonyl fluorophosphonate;
  • NAPE, N-acyl-phosphatidylethanolamine;
  • NSCC, non-selective cation channel;
  • OX1, orexin 1 receptor;
  • OX2, orexin 2 receptor;
  • PA, phosphatidic acid;
  • PC, phosphatidylcholine;
  • PC-PLC, PC-specific PLC;
  • PDK1,phosphoinositide-dependent kinase 1;
  • PI3K, phosphoinositide-3-kinase;
  • PI, phosphatidylinositol;
  • PIs,phosphatidylinositols (including differentially phosphorylated species PI, PIP, PIP2 and PIP3);
  • PIP,phosphatidylinositolmonophosphate;
  • PIP2, phosphatidylinositol-4,5-bisphosphate;
  • PIP3,phosphatidylinositol-3,4,5-trisphosphate;
  • PKB, PKC and PKD, protein kinase B, C and D, respectively;
  • PLA1, PLA2, PLB, PLC and PLD, phospholipase A1, A2, B, C and D, respectively;
  • pyrrophenone, a cPLA2α/ζ inhibitor;
  • TRP (channel), transient receptor potential (channel);
  • U73122, a PLC inhibitor

Figures and tables from this article:

Full-size image (60 K)
Fig. 1. Phospholipase signaling and signal pathway interaction. (A) OX1 receptor stimulation-induced phospholipase pathways in CHO cells. (B) Some possible conversions of the lipid messengers. Please observe that the same messengers (e.g. DAG) from different pathways may not be equal (different fatty acid composition). (C) PIP2 and signaling. NCX and some K+ channels (VGKC) require PIP2 for activity and some NSCCs are inhibited and some are stimulated by PIP2. PIP2 is required by PLD and it also stimulates cPLA2α. PLC hydrolyses PIP2 and thus reduces PIP2levels while PLD signaling increases PIP2 synthesis. FFA, free fatty acid. Responses downstream of PIP2 metabolism are not shown (i.e. PLC and PI3K cascades).
Full-size image (28 K)
Fig. 2. (Putative) Targets for phospholipase-generated messengers in orexin receptor signaling. (A) cPLA2 signaling contributes to Ca2+ influx in OX1-expressing CHO cells. (B) OX1-expressing CHO cells show robust activation of PLD via a nPKC, but the role of PLD signaling is unknown so far. It is also unknown how the nPKC is activated (Section 3.2). (C) PLC signaling has multiple roles in orexin receptor responses. DAG may directly regulate some NSCCs. DAG also activates PKC, which may activate NCX, NSCCs and Ca2+ channels (VGCC) and inhibit K+ channels. PLC signaling may regulate ion channels and NCX also by reducing PIP2 (see Fig. 1). DAGL degrades DAG to 2-AG, which exits the cells and acts as a CB1 receptor agonist, and 2-AG degradation releases AA (not shown). IP3 acts as an IP3 receptor ligand releasing Ca2+ into the cytosol (not shown).
Corresponding author contact information
Tel.: +358 9 191 57024; fax: +358 9 191 57033.

Copyright © 2013 Published by Elsevier Masson SAS

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