Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/32976
Title: Characterisation of P2Y(12) receptor responsiveness to cysteinyl leukotrienes
Authors: Foster, Holly R.
Fuerst, Elisabeth
Lee, Tak H.
Cousins, Davis J.
Woszczek, Grzegorz
First Published: 5-Mar-2013
Publisher: Public Library of Science
Citation: PLoS One, 2013, 8 (3):e58305
Abstract: Leukotriene E4 (LTE4), the most stable of the cysteinyl leukotrienes (cysLTs), binds poorly to classical type 1 and 2 cysLT receptors although in asthmatic individuals it may potently induce bronchial constriction, airway hyperresponsiveness and inflammatory cell influx to the lung. A recent study has suggested that the purinergic receptor P2Y12 is required for LTE4 mediated pulmonary inflammation in a mouse model of asthma and signals in response to cysLTs. The aim of the study was to characterise the responsiveness of human P2Y12 to cysteinyl leukotrienes. Models of human CysLT1, CysLT2 and P2Y12 overexpressed in HEK293, CHO cells and human platelets were used and responsiveness to different agonists was measured using intracellular calcium, cAMP and β-arrestin recruitment assays. CysLTs induced concentration dependent calcium mobilisation in cells overexpressing CysLT1 and CysLT2 but failed to induce any calcium response in cells expressing P2Y12 or P2Y12+ Gα16. In contrast, selective P2Y12 agonists ADP and 2-MeS-ADP induced specific calcium flux in cells expressing P2Y12+ Gα16. Similarly, specific response to 2-MeS-ADP, but not to cysLTs was also observed in cells expressing P2Y12 when intracellular cAMP and β-arrestin signalling were analysed. Platelets were used as a model of human primary cells expressing P2Y12 to analyse potential signalling and cell activation through P2Y12 receptor or receptor heterodimers but no specific LTE4 responses were observed. These results show that LTE4 as well as other cysLTs do not activate intracellular signalling acting through P2Y12 and suggest that another LTE4 specific receptor has yet to be identified.
DOI Link: 10.1371/journal.pone.0058305
eISSN: 1932-6203
Links: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058305
http://hdl.handle.net/2381/32976
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2013 Foster et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ( http://creativecommons.org/licenses/by/3.0/ )
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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