IP3-independent signalling of OX1 orexin/hypocretin receptors to Ca2+ influx and ERK

Biochem Biophys Res Commun. 2007 Feb 9;353(2):475-80. doi: 10.1016/j.bbrc.2006.12.045. Epub 2006 Dec 15.


OX1 orexin receptors (OX1R) have been shown to activate receptor-operated Ca2+ influx pathways as their primary signalling pathway; however, investigations are hampered by the fact that orexin receptors also couple to phospholipase C, and therewith inositol-1,4,5-trisphosphate (IP3)-dependent Ca2+ release. We have here devised a method to block the latter signalling in order to focus on the mechanism of Ca2+ influx activation by OX1R in recombinant systems. Transient expression of the IP3-metabolising enzymes IP3-3-kinase-A (inositol-1,4,5-trisphosphate-->inositol-1,3,4,5-tetrakisphosphate) and type I IP3-5-phosphatase (inositol-1,4,5-trisphosphate-->inositol-1,4-bisphosphate) almost completely attenuated the OX1R-stimulated IP3 elevation and Ca2+ release from intracellular stores. Upon attenuation of the IP3-dependent signalling, the receptor-operated Ca2+ influx pathway became the only source for Ca2+ elevation, enabling mechanistic studies on the receptor-channel coupling. Attenuation of the IP3 elevation did not affect the OX1R-mediated ERK (extracellular signal-regulated kinase) activation in CHO cells, which supports our previous finding of the major importance of receptor-operated Ca2+ influx for this response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / pharmacokinetics*
  • Cricetinae
  • Cricetulus
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Orexin Receptors
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Neuropeptide / metabolism*
  • Signal Transduction / physiology*


  • Inositol 1,4,5-Trisphosphate Receptors
  • Orexin Receptors
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Extracellular Signal-Regulated MAP Kinases
  • Calcium