In:
British Journal of Pharmacology, Wiley, Vol. 159, No. 1 ( 2010-01), p. 212-221
Abstract:
Background and purpose: We have previously shown that lipid mediators, produced by phospholipase D and C, are generated in OX 1 orexin receptor signalling with high potency, and presumably mediate some of the physiological responses to orexin. In this study, we investigated whether the ubiquitous phospholipase A 2 (PLA 2 ) signalling system is also involved in orexin receptor signalling. Experimental approach: Recombinant Chinese hamster ovary‐K1 cells, expressing human OX 1 receptors, were used as a model system. Arachidonic acid (AA) release was measured from 3 H‐AA‐labelled cells. Ca 2+ signalling was assessed using single‐cell imaging. Key results: Orexins strongly stimulated [ 3 H]‐AA release (maximally 4.4‐fold). Orexin‐A was somewhat more potent than orexin‐B (pEC 50 = 8.90 and 8.38 respectively). The concentration–response curves appeared biphasic. The release was fully inhibited by the potent cPLA 2 and iPLA 2 inhibitor, methyl arachidonyl fluorophosphonate, whereas the iPLA 2 inhibitors, R‐ and S‐bromoenol lactone, caused only a partial inhibition. The response was also fully dependent on Ca 2+ influx, and the inhibitor studies suggested involvement of the receptor‐operated influx pathway. The receptor‐operated pathway, on the other hand, was partially dependent on PLA 2 activity. The extracellular signal‐regulated kinase, but not protein kinase C, were involved in the PLA 2 activation at low orexin concentrations. Conclusions and implications: Activation of OX 1 orexin receptors induced a strong, high‐potency AA release, possibly via multiple PLA 2 species, and this response may be important for the receptor‐operated Ca 2+ influx. The response coincided with other high‐potency lipid messenger responses, and may interact with these signals.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2010.159.issue-1
DOI:
10.1111/j.1476-5381.2009.00535.x
Language:
English
Publisher:
Wiley
Publication Date:
2010
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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