Ramanjaneya, Manjunath, Conner, Alex C., Chen, Jing, Kumar, Prashanth, Brown, James E. P., Joehren, Olaf, Lehnert, Hendrik, Stanfield, Peter R. and Randeva, Harpal S.. (2009) Orexin-stimulated MAP kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells : diverse roles for orexins A and B. Journal of Endocrinology, Vol.202 (No.2). pp. 249-261. ISSN 0022-0795

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Abstract

Orexins A and B (ORA and ORB) are neuropeptide hormones found throughout the central nervous system and periphery. They are required for a host of physiological processes including mitogen-activated protein kinase (MAPK) regulation, steroidogenesis, appetite control and energy regulation. While some signalling mechanisms have been proposed for individual recombinant orexin receptors in generic mammalian cell types, it is clear that the peripheral effects of orexin are spatially and temporally complex. This study dissects the different G-protein signalling and MAPK pathways activated in a pluripotent human adrenal H295R cell line capable of all the physiological steps involved in steroidogenesis. Both extracellular receptor kinase 1/2 (ERK1/2) and p38 were phosphorylated rapidly with a subsequent decline, in a time- and dose-dependent manner, in response to both ORA and ORB. Conversely, there was little or no direct activation of the ERK5 or JNK pathway. Analysis using signalling and MAPK inhibitors as well as receptor-specific antagonists determined the precise mediators of the orexin response in these cells. Both ERK1/2 and p38 activation were predominantly G(q)- and to a lesser extent G(s)-mediated; p38 activation even had a small G(i)-component. Effects were broadly comparable for both orexin sub-types ORA and ORB and although most of the effects were transmitted through the orexin receptor-1 subtype, we did observe a role for orexin receptor-2-mediated activation of both ERK1/2 and p38. Cortisol secretion also differed in response to ORA and ORB. These data Suggest multiple roles for orexin-mediated MAPK activation in an adrenal cell-line, this complexity may help to explain the diverse biological actions of orexins with wide-ranging consequences for Our understanding of the mechanisms initiated by these steroidogenic molecules. journal of Endocrinology (2009) 202, 249-261

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Journal of Endocrinology
Publisher:	Society for Endocrinology
ISSN:	0022-0795
Date:	August 2009
Volume:	Vol.202
Number:	No.2
Number of Pages:	13
Page Range:	pp. 249-261
Identification Number:	10.1677/JOE-08-0536
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Coventry General Charities
URI:	http://wrap.warwick.ac.uk/id/eprint/16800

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