SFEBES2009 Poster Presentations Steroids (36 abstracts)
Orexin-stimulated MAP Kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells: differential regulation by orexin A and orexin B
Jing Chen 1 , Manjunath Ramanjaneya 2 , Alex Conner 1 , Prashanth Kumar 1 , James Brown 1 , Olaf Johren 2 , Hendrik Lehnert 2 , Peter Stanfield 1 & Harpal Randeva 1
1University of Warwick, Coventry, UK; 2Univeristy of Lübeck, Lübeck, Germany.
Orexin-A and orexin-B orchestrate their diverse central and peripheral effects via two G-protein coupled receptors, OX1R and OX2R, which activate multiple G-proteins. They are involved in a host of physiological processes including, steroidogenesis, appetite control and energy regulation. Whilst 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 current study dissects the different G-protein signalling and MAPK pathways involved in a pluripotent human adrenal H295R cell-line capable of producing all the major adrenal steroid hormones. Both ERK1/2 and p38 were phosphorylated rapidly with a subsequent decline, in a time- and dose-dependent manner, in response to both orexin A and orexin B. Conversely there was little or no direct activation of the ERK5 or JNK pathways. A comprehensive analysis using signalling and MAPK inhibitors, dominant-negative G protein analysis, 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 Gq- and to a lesser extent Gs-mediated; p38 activation even had a small Gi-component. Effects were broadly comparable for both ORA and ORB, and although most of the effects were transmitted through the OX1 receptor sub-type, we did observe a role for OX2R-mediated activation of both ERK1/2 and p38. Cortisol secretion also differed in response to ORA and ORB. All together these results suggests multiple roles for orexin-mediated MAPK activation, this complexity may help explain the diverse biological actions of orexins and has wide-ranging consequences for our understanding of the mechanisms initiated by these steroidogenic molecules.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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