Insights into the pharmacological relevance of lysophospholipid receptors

Abstract

The discovery of lysophospholipid (LP) 7-transmembrane, G protein-coupled receptors (GPCRs) that began in the 1990s, together with research into the functional roles of the major LPs known as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), have opened new research avenues into their biological processes and mechanisms. Major examples of LP signalling effects include embryogenesis, nervous system development, vascular development, uterine implantation, immune cell trafficking, and inflammatory reactions. LP signalling also influences the pathophysiology of many diseases including cancer, autoimmune and inflammatory diseases, which indicate that LP receptors may be attractive targets for pharmacological therapies. A key example of such a therapeutic agent is the S1P receptor modulator FTY720, which upon phosphorylation and continued drug exposure, acts as an S1P receptor functional antagonist. This compound (also known as fingolimod or Gilenya) has recently been approved by the FDA for the treatment of relapsing forms of multiple sclerosis. Continued basic and translational research on LP signalling should provide novel insights into both basic biological mechanisms, as well as novel therapeutic approaches to combat a range of human diseases.

Figure 1

The molecular structure of major lysophospholipids. Space-filling molecular models and structural formulas of LPA, S1P, LPC, SPC, LPS and LPE and some major analogues are shown. High-affinity LP receptors are indicated in parentheses under the name of each ligand.

Figure 2

The network of LPA and S1P signalling through G protein-coupled receptors. Each LPA and S1P receptor couples to specific classes of G proteins. Ligand-binding activates or inhibits downstream second messenger molecules, and the most prominent cellular effects are illustrated. Rock, Rho-associated kinase; SRF, serum response factor; IP3, inositol 1,4,5-trisphosphate; PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositol 3-kinase; DAG, diacylglycerol.