Lysophosphatidic Acid as a Novel Lipid Mediator

This chapter briefly discusses the current state of knowledge and understanding of the multiple biochemical and biological activities of LPA, with emphasis on its formation, site of action, and activation of G protein-mediated signal transduction cascades. Well-known examples of phospholipid-derived signaling molecules include diacylglycerol, inositol triphosphate, and arachidonate and its active metabolites, all of which are produced rapidly in the activated cells. The simplest naturally occurring phospholipid and lysophosphatidic acid (LPA) show striking biological activities when added to the appropriate target cells at doses far below its critical micelle concentration. Exogenous LPA, at submicromolar doses, evokes a remarkably wide range of hormone- and growth factor-like effects in many different cell types. Although exogenous LPA is metabolized partially to monoacylglycerol, the latter metabolite has no biological activity. LPA- and thrombin-induced changes in neuronal cell shape appear to be mediated by the “contraction” of the cortical actin cytoskeleton, with no direct involvement of microtubules. As for the signaling mechanism responsible for this novel action of LPA and thrombin in N1E-115 cells, as in many other cells, LPA stimulates phosphoinositide hydrolysis, leading to calcium mobilization and activation of protein kinase C. It is required to establish the amino acid sequence of the putative LPA cell surface receptor, either through protein purification or, perhaps more straight forwardly, by expression cloning in the COS cells.