Decanoyl lysophosphatidic acid induces platelet aggregation through an extracellular action. Evidence against a second messenger role for lysophosphatidic acid

Abstract

Platelets rapidly convert 1,2-didecanoyl-sn-glycerol into its corresponding phosphatidic acid and lysophosphatidic acid derivatives, thereby providing a means of introducing these two compounds into platelets. 1-Decanoyl-2-lyso-3-sn-phosphatidic acid, when added directly to platelets, induced platelet aggregation and raised intracellular Ca2+ levels at concentrations of 0.3 microM upwards, but was without effect when formed intracellularly from 1,2-didecanoylglycerol at an estimated concentration of approx. 47 microM. This indicates that the site of platelet activation by lysophosphatidic acid is extracellular. A concentration of thrombin (0.2 unit/ml), which produced maximal platelet aggregation, caused an estimated intracellular formation of 20 microM-lysophosphatidic acid in the presence of 2 mM-Ca2+; however, there was no detectable release of lysophosphatidic acid into the bathing medium. Lysophosphatidic acid, therefore, may not be an intracellular second messenger involved in platelet aggregation by thrombin.

Activity of 2-Substituted Lysophosphatidic Acid (LPA) Analogs at LPA Receptors: Discovery of a LPA1/LPA3Receptor Antagonist

“…Transient rises in blood pressure in rats and guinea pigs after intravenous LPA injection have also been documented (Tokumura et al, 1978). LPA is released by activated platelets and accumulates in serum to low micromolar levels (Schumacher et al, 1979;Simon et al, 1982;Watson et al, 1985). The induction of platelet aggregation and fibroblast recruitment along with its mitogenic capabilities implicate this lipid as a wound healing hormone (Moolenaar, 1995).…”

Human Lysophosphatidic Acid Acyltransferase

“…Because activated platelets copiously secrete the mediator, it has been suggested that aggregated platelets are the primary source of the serum LPA (14,18). This source, coupled with the mitogenic and chemotactic properties of LPA, has prompted the hypothesis that the phospholipid is an important mediator of wound healing (12).…”

Recombinant Human G Protein-Coupled Lysophosphatidic Acid Receptors Mediate Intracellular Calcium Mobilization

“…Extracellular addition of LPA results in increases in [Ca 2ϩ ] i in many cell types, including fibroblasts, platelets, vascular smooth muscle cells, neuronal cells, astrocytes, mesangial cells, many tumor cells, and X. laevis oocytes (Watson et al, 1985;Jalink et al, 1990;Durieux et al, 1992;Inoue et al, 1995;Jalink et al, 1995;Xu et al, 1995;Keller et al, 1997;Seewald et al, 1997). LPAinduced Ca 2ϩ mobilization can be transduced through both PTX-sensitive and PTX-insensitive G protein activation of PLC.…”