diacylglycerol-pyrophosphate and lysophosphatidic-acid

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is a simple phospholipid but displays an intriguing cell biology that is mediated via interactions with both G-protein-coupled seven transmembrane receptors (GPCRs) and nuclear hormone receptors. So far, seven GPCRs (LPA(1-5) and recently reported GPR87/LPA(6) and P2Y5/LPA(7)) and a nuclear hormone receptor, PPARgamma, have been identified. LPA is predominantly produced in blood and a plasma enzyme, autotaxin, is involved in its production. Recent gene manipulating studies of these proteins have shown that LPA is involved in both pathological and physiological states including brain development, neuropathy pain, implantation, protection against radiation-induced intestinal injury and blood vessel formation. In addition, lipids similar to LPA, such as sphingosine 1-phosphate (S1P) and 2-arachidonylglycerol (2-AG), share common cellular signaling pathways with LPA and are now considered as promising targets of human therapy including immunosuppressant and anti-obesity drugs. Thus, LPA is now one of the most attractive targets for prevention and treatment of various diseases. Receptor-selective antagonists and agonists as well as inhibitors of LPA producing enzymes are undoubtedly useful. Recognition of the ligand, LPA, by each receptor seems to be quite different, as LPA species with various fatty acids at either the sn-1 or sn-2 position of the hydroxy residue activate each receptor quite differently. In the last decade a series of LPA analogs in which the sn-1 or sn-2 hydroxy, acyl chain, glycerol and phosphate group are modified have been created and evaluated by several laboratories. Here we review recent advances in the development of LPA-receptor targeted compounds (agonists and antagonists) and anti-autotaxin inhibitors.

Topics: Animals; Drug Design; Humans; Lysophospholipids; Molecular Structure; Receptors, Lysophosphatidic Acid

Phylogenetic analysis of transmembrane regions of GPCRs using PHYLIP indicated that the orphan receptor P2Y(10) receptor was classified into the cluster consisting nucleotide and lipid receptors. Based on the results, we studied the abilities of nucleotides and lipids to activate the P2Y(10) receptors. As a result, sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) evoked intracellular Ca(2+) increases in the CHO cells stably expressing the P2Y(10) fused with a G(16alpha) protein. These Ca(2+) responses were inhibited by S1P receptor and LPA receptor antagonists. The introduction of siRNA designed for P2Y(10) receptor into the P2Y(10)-CHO cells effectively blocked both S1P- and LPA-induced Ca(2+) increases. RT-PCR analysis showed that the mouse P2Y(10) was expressed in reproductive organs, brain, lung and skeletal muscle, suggesting the receptor plays physiological roles throughout the whole body. In conclusion, the P2Y(10) receptor is the first receptor identified as a dual lysophospholipid receptor.

Topics: Amino Acid Sequence; Animals; Calcium; CHO Cells; Cricetinae; Cricetulus; Humans; Ligands; Lysophospholipids; Mice; Molecular Sequence Data; Phylogeny; Protein Conformation; Receptors, Lysophosphatidic Acid; Receptors, Lysosphingolipid; Receptors, Purinergic P2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Sequence Analysis, Protein; Sphingosine; Tissue Distribution

In CHO cells stably expressing the GPR87 fused with a G16alpha protein, lysophosphatidic acid (LPA) evoked an intracellular Ca(2+) increase in a high affinity manner. The Ca(2+) increase was reversibly blocked by the LPA receptor antagonists and inhibited by pretreatment of the cells with GPR87-specific siRNAs. GPR87 was shown to be closer to the P2Y and P2Y-related receptors than LPA receptors by ClustalW analyses. However, none of nucleotides and their derivatives activated GPR87. The human gpr87 is located on the chromosome 3q25 in a cluster containing p2y12,13,14. RT-PCR analysis showed that the mouse GPR87 was expressed in placenta, ovary, testis, prostate, brain, and skeletal muscle. The 3D model of GPR87-LPA complex indicated that the ligand interacted with R115 and K296 of GPR87, which are well conserved in the P2Y receptors. These results suggest that the GPR87 is a LPA receptor which evolved from a common ancestor of P2Y receptors.

Topics: Animals; Binding Sites; Calcium; CHO Cells; Cricetinae; Cricetulus; Electrophoresis, Polyacrylamide Gel; Female; Gene Expression Profiling; GTP-Binding Protein alpha Subunits; Humans; Intracellular Fluid; Isoxazoles; Lysophospholipids; Male; Mice; Mice, Inbred BALB C; Models, Molecular; Propionates; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Uridine Triphosphate