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

Sattikar, Afrah; Dowling, Mark R,; Rosethorne, Elizabeth M.

Abstract

Background and Purpose

Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a GPCR that responds to the endogenous lipid mediator, lysophosphatidic acid (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 ERK phosphorylation.
Key Results

These analyses demonstrated that the 16:0, 17:0, 18:2 and C18:1 LPA analogues appear to exhibit ligand bias between ERK phosphorylation and calcium mobilization when compared with 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 shown by 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.

Citation

Sattikar, A., Dowling, M. R., & Rosethorne, E. M. (2017). Endogenous lysophosphatidic acid (LPA1) receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts. British Journal of Pharmacology, 174(3), 227-237. https://doi.org/10.1111/bph.13671

• Journal Article Type: Article
• Acceptance Date: Nov 10, 2016
• Online Publication Date: Jan 6, 2017
• Publication Date: Feb 1, 2017
• Deposit Date: Mar 22, 2017
• Publicly Available Date: Mar 22, 2017
• Journal: British Journal of Pharmacology
• Print ISSN: 0007-1188
• Electronic ISSN: 1476-5381
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 174
• Issue: 3
• Pages: 227-237
• DOI: https://doi.org/10.1111/bph.13671
• Public URL: https://nottingham-repository.worktribe.com/output/970747
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1111/bph.13671/full
• Additional Information: This is the peer reviewed version of the following article: Sattikar, A., Dowling, M. R., and Rosethorne, E. M. (2017) Endogenous lysophosphatidic acid (LPA1) receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts. British Journal of Pharmacology, 174: 227–237, which has been published in final form at http://dx.doi.org/10.1111/bph.13671. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
• Contract Date: Mar 22, 2017