Tang, Jiyou, Chen, J. (Jing), Ramanjaneya, Manjunath, Punn, Anu, Conner, Alex C. and Randeva, Harpal S.. (2008) The signalling profile of recombinant human orexin-2 receptor. Cellular Signalling, Vol.20 (No.9). pp. 1651-1661. ISSN 0898-6568

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Abstract

Orexin-A and orexin-B orchestrate their diverse central and peripheral effects via two G-protein coupled receptors, OX1R and OX2R, which activate multiple C-proteins. In many tissues, orexins activate extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinase (MAPK); however, the mechanism by which OX2R alone mediates MAPK activation is not understood. This study describes the intracellular signalling pathways involved in OX2R-mediated ERK1/2 and p38 MAPK activation. In HEK-293 cells stably over-expressing recombinant human OX2R, orexin-A/B resulted in a rapid, dose and time dependent increase in activation of ERK1/2 and p38 MAPK, with maximal activation at 10 min for ERK1/2 and 30 min for p38 MAPK. Using dominant-negative G-proteins and selective inhibitors of intracellular signalling cascades, we determined that orexin-A and orexin-B induced ERK1/2 and p38 MAPK activation through multiple G-proteins and different intracellular signalling pathways. ERK1/2 activation involves Gq/phospholipase C (PLC)/protein kinase C (PKC), Gs/adenylyl cyclase (AC)/cAMP/protein kinase A (PKA) and Gi cascades; however, the Gq/PLC/PKC pathway, as well as PKA is not required for OX2R-mediated p38 MAPK activation. Interestingly, orexin-B-induced ERK1/2 activation is predominantly mediated through the Gq/PLC/PKC pathway. In conclusion, this is the first comprehensive signalling study of the human OX2R recombinant receptor, showing ERK1/2 and p38 MAPK activation are regulated by differential signalling pathways in HEK-293 cells, and that the ERK1/2 activation is severely affected by naturally occurring mutants associated with narcolepsy. Moreover, it is evident that the human OX2R has ligand specific effects, with orexin-B being more potent in this transfected system and this distinct modulation of the MAPKs through OX2R, may translate to the regulation of diverse biological actions of orexins. (C) 2008 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Orexins, G proteins, Cellular signal transduction
Journal or Publication Title:	Cellular Signalling
Publisher:	Elsevier
ISSN:	0898-6568
Date:	September 2008
Volume:	Vol.20
Number:	No.9
Number of Pages:	11
Page Range:	pp. 1651-1661
Identification Number:	10.1016/j.cellsig.2008.05.010
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	British Heart Foundation, Coventry General Charities
Grant number:	PG/03/131/16192 (BHF)
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URI:	http://wrap.warwick.ac.uk/id/eprint/29548

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