A Subfamily of G Protein-Coupled Cellular Receptors for Lysophospholipids and Lysosphingolipids

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Abstract
The lipid phosphoric acids, including lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are generated from membranes of many different types of stimulated cells. In extracellular fluids, these distinctive phospholipids are potent mediators of growth and many other cellular functions,1,2 and intracellularly serve as messengers of diverse signals from cell-surface receptors.3 Both lipid phosphoric acid mediators are characterized by widespread cellular production, often separate synthetic pathways for the intracellular and secreted pools, micromolar maximal concentrations in serum and some other fluids, high levels of binding to albumin and some other serum proteins, and biodegradation by one or more specific enzymatic mechanisms. The multicomponent pathway for biosynthesis of secreted LPA is distinct from those which produce LPA in cellular metabolism, and is one well-described example of the compartmental generation of lipid phosphoric acids. Efficient generation of LPA for secretion requires sequential release of plasma membrane vesicles from stimulated leukocytes, platelets or other cells, exposure of the vesicles to sphingomyelinase, production of phosphatidic acid (PA) by phospholipase (PL) C- and/or D-dependent mechanisms, and conversion of PA to LPA by a secretory PLA2.4 LPA is enzymatically inactivated by lysophospholipases, acetyltransferases and phosphatidate phosphohydrolases of differing specificities, whereas SIP is cleaved predominantly by a lyase.2,5 The steady-state tissue and fluid levels of LPA and SIP are determined by the ratio of enzymatic activities of the biosynthetic and degradative systems. LPA has many potent effects on cellular proliferation and differentiation, cellular migration, platelet shape change and aggregation, smooth muscle tone, and activities of membrane ion channels and enzymes.1 The broad range of effects of S1P is similar to that of LPA, but S1P is a more prominent mediator of endothelial cell adherence and junction formation, and neurite retraction.2 Early results of studies of lipid phosphoric acids in cell death suggest that S1P and LPA may be active inhibitors of apoptosis. The capacity to suppress formation of intracellular S1P with selective inhibitors of sphingosine kinase has facilitated investigations of its possible role as an intracellular messenger,3 whereas any similar functions of LPA and PA are less clear. The different contributions of S1P exhibit cellular specificity. Intracellular signaling functions of S1P are best appreciated in fibroblasts and mast cells, and extracellular mediator activities predominate in platelets, neurons, cardiac myocytes and macrophages.