Lipid signaling cascades of orexin/hypocretin receptors

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 OX2 receptors, 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: 2-AG; 2-arachidonoylglycerol; AA; CNS; DAG; DAG lipase; DAGL; DOG; ERK; Endocannabinoid; G-protein-coupled receptor; GPCR; GPL; Hypocretin; IP(3); Ion fluxes; KB-R7943; MAFP; N-acyl-phosphatidylethanolamine; N-arachidonoylethanolamine; NAPE; NSCC; OX(1); OX(2); Orexin; PA; PC; PC-PLC; PC-specific PLC; PDK1; PI; PI3K; PIP; PIP(2); PIP(3); PIs; PKB, PKC and PKD; PLA(1), PLA(2), PLB, PLC and PLD; Phospholipase; TRP (channel); U73122; a NCX inhibitor; a PLC inhibitor; a cPLA(2)α/ζ inhibitor; anandamide; arachidonic acid; cPLA(2) and iPLA(2); central nervous system; cytosolic (Ca(2+)-dependent) and intracellular (Ca(2+)-independent) PLA(2), respectively; diacylglycerol; dioctanoylglycerol; extracellular signal-regulated kinase; glycerophospholipid; inositol-1,4,5-trisphosphate; lyso(glycero)phospholipid; lysoGPL; lysoPA; lysophosphatidic acid; methyl arachidonyl fluorophosphonate; non-selective cation channel; orexin 1 receptor; orexin 2 receptor; phosphatidic acid; phosphatidylcholine; phosphatidylinositol; phosphatidylinositol-3,4,5-trisphosphate; phosphatidylinositol-4,5-bisphosphate; phosphatidylinositolmonophosphate; phosphatidylinositols (including differentially phosphorylated species PI, PIP, PIP(2) and PIP(3)); phosphoinositide-3-kinase; phosphoinositide-dependent kinase 1; phospholipase A(1), A(2), B, C and D, respectively; protein kinase B, C and D, respectively; pyrrophenone; transient receptor potential (channel).