Lysophosphatidic acid-induced Ca2+ mobilization in human A431 cells: structure-activity analysis
| Autor: | Marie-Françoise Simon, Hugues Chap, W J van Blitterswijk, Kees Jalink, G. A. Van Der Marel, Trudi Hengeveld, S Mulder, J. H. Van Boom, Wouter H. Moolenaar, Friso R. Postma |
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| Rok vydání: | 1995 |
| Předmět: |
Biology
Phospholipase Biochemistry Structure-Activity Relationship chemistry.chemical_compound Organophosphorus Compounds Sphingosine Lysophosphatidic acid Tumor Cells Cultured Animals Humans Receptor Molecular Biology Antagonist Esters Cell Biology Lipid signaling chemistry Calcium lipids (amino acids peptides and proteins) Lysophospholipids biological phenomena cell phenomena and immunity A431 cells Intracellular Signal Transduction Research Article |
| Zdroj: | Biochemical Journal. 307:609-616 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj3070609 |
| Popis: | Lysophosphatidic acid (LPA; 1-acyl-sn-glycero-3-phosphate) is a platelet-derived lipid mediator that activates its own G-protein-coupled receptor to trigger phospholipase C-mediated Ca2+ mobilization and other effector pathways in numerous cell types. In this study we have examined the structural features of LPA that are important for activation of the Ca(2+)-mobilizing receptor in human A431 carcinoma cells, which show an EC50 for oleoyl-LPA as low as 0.2 nM. When the acyl chain at the sn-1 position is altered, the rank order of potency is oleoyl-LPA > arachidonoyl-LPA > linolenoyl-LPA > linoleoyl-LPA > stearoyl-LPA = palmitoyl-LPA > myristoyl-LPA. The shorter-chain species, lauroyl- and decanoyl-LPA, show little or no activity. Ether-linked LPA (1-O-hexadecyl-sn-glycero-3-phosphate) is somewhat less potent than the corresponding ester-linked LPA; its stereoisomer is about equally active. Deletion of the glycerol backbone causes a 1000-fold decrease in potency. Replacement of the phosphate group in palmitoyl-LPA by a hydrogen- or methyl-phosphonate moiety results in complete loss of activity. A phosphonate analogue with a methylene group replacing the oxygen at sn-3 has strongly decreased activity. All three phosphonate analogues induce cell lysis at doses > 15 microM. Similarly, the methyl and ethyl esters of palmitoyl-LPA are virtually inactive and become cytotoxic at micromolar doses. None of the LPA analogues tested has antagonist activity. Sphingosine 1-phosphate, a putative messenger with some structural similarities to LPA, elicits a transient rise in intracellular [Ca2+] only at micromolar doses; however, cross-desensitization experiments indicate that sphingosine 1-phosphate does not act through the LPA receptor. The results indicate that, although many features of the LPA structure are important for optimal activity, the phosphate group is most critical, suggesting that this moiety is directly involved in receptor activation. |
| Databáze: | OpenAIRE |
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