Intercellular Lipid Mediators and GPCR Drug Discovery

Abstract

G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed.

Keywords: Drug discovery; Fatty acid; GPCR; Lipid; Lipid mediator; Lysophospholipid.

Fig. 1.. Schematic diagram of lipid-mediated signal transduction pathways. For cellular responses, LPA activates LPA₃, which leads to activation of phospholipase C (PLC). Activated PLC produces IP₃ and diacylglycerol (DAG), DAG activates protein kinase C (PKC), and IP₃ mobilizes Ca²⁺ from internal Ca²⁺ stores by activating IP₃ receptors. The resulting increase in intracellular Ca²⁺ activates calmodulin-dependent protein kinases. Alternatively, S1P activates S1P₁, which leads to inhibition of adenylyl cyclase and the activations of ras, MAPK, PI3K, and AKT via Gi proteins. For desensitization, S1P activates S1P₁, which leads to GRK2 activation, S1P₁ phosphorylation, and to the recruitment β-arrestins by S1P₁. The recruited β-arrestins then inhibit S1P₁-G protein coupling.

Fig. 2.. Phylogenetic tree of lipid GPCRs. The phylogenetic tree was constructed using the Clustal Omega multiple sequence alignment and TreeIllustrator programs.