Endogenous LPA1 receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts

2016 
Background and Purpose Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a G protein-coupled receptor (GPCR) that responds to the endogenous lipid mediator lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA1 receptor, which predominantly couples to Gq/11, Gi/o and G12/13 proteins. This promiscuity of coupling raises the possibility that some of the LPA analogues may bias the LPA1 receptor towards one signalling pathway over another. Experimental Approach Here we have explored the signalling profiles of a range of LPA analogues in HLF that endogenously express the LPA1 receptor. HLF were treated with LPA analogues, and receptor activation monitored via calcium mobilization and extracellular signal-regulated kinase (ERK) phosphorylation. Key Results These analyses demonstrated that 16:0, 17:0, 18:2 and C18:1 LPA analogues appear to exhibit ligand bias between ERK phosphorylation and calcium mobilization when compared to 18:1 LPA, one of the most abundant forms of LPA that has been found in human plasma. Conclusion and Implications The importance of LPA as a key signalling molecule is apparent due to its widespread occurrence in biological fluids and its association with disease conditions such as fibrosis and cancer. These findings have important, as yet unexplored, implications for the (patho) physiological signalling of the LPA1 receptor, as it may be influenced not only by the concentration of endogenous ligand but the isoform as well. This article is protected by copyright. All rights reserved.
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