Lysophospholipid signaling: Beyond the EDGs

As our understanding of the myriads of biological effects caused by lysophospholipids expands, we become witnesses to another miracle of nature that has endowed the simplest lysophospholipids with functions seemingly ubiquitous to every mammalian cell. A decade after the discovery of the EDG family lysophospholipid receptors, the field has gained unimaginable impetus explaining the biological effects of sphingosine-1-phosphate and lysophosphatidic acid (LPA). The discovery of LPA receptors in the purinergic G-protein-coupled receptor (GPCR) gene cluster refined this picture and added complexity to our concepts of lysophospholipid cell signaling. The intracellular lysophospholipid targets – identified and not yet identified – make us realize the dual mediator and second messenger roles of lysophospholipids. In this paper we provide new data obtained concerning LPA-elicited responses using cell lines naturally lacking or intentionally knocked out of many of the known LPA GPCR, widely used by investigators in the field as cells with LPA receptor “null background.” Our observations raise caution about the lack of LPA responsiveness in these cells and underline the unprecedented complexity and redundancy of lysophospholipid-evoked cellular responses.