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Vol. 63, Issue 3, 471-477, March 2003
Novartis Horsham Research Centre (C.E.J., S.H., P.T., J.T., R.K.,
S.C., G.J., P.F.), Horsham West Sussex, UK; Novartis Pharma AG, Basel,
Switzerland (L.T., K.S., R.B.); and Novartis Pharmaceuticals
Corporation, Summit, New Jersey, USA. (N.R.N, U.B.)
Using a bioinformatics approach, we have isolated a novel
G-protein-coupled receptor (GPCR), R527, and have demonstrated that this receptor shows no significant homology to previously deorphanized GPCRs. Quantitative reverse transcription-polymerase chain reaction analysis of the expression of GPCR R527 indicated a very high level of
mRNA expression in eosinophils, with high expression also detected in
neutrophils and lung macrophages. Stable cell lines were generated
expressing this receptor together with the G-protein 
-subunit
G16. These cells were used to screen an agonist collection in a calcium mobilization assay and
5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) was identified as a putative ligand.
5(S)-Hydroxyperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid was also shown to activate the receptor, whereas the leukotrienes LTB4, LTC4, LTD4, and
LTE4 failed to elicit a response. In cAMP assays, pertussis
toxin reversed the inhibitory effects of 5-oxo-ETE on cAMP production,
indicating that the receptor is Gi-coupled. The GPCR
R527 shows pharmacological properties similar to those of the
previously described 5-oxo-ETE receptor expressed on eosinophils, neutrophils, and monocytes. These cell types show chemotactic responses
to 5-oxo-ETE, and this eicosanoid has been proposed to play a key role
in the inflammatory response. The molecular identification of a
receptor binding 5-oxo-ETE will expand our understanding of the
physiological role of this mediator and may provide new therapeutic opportunities.
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