The biologically active phospholipid, lysophosphatidic acid, induces phosphatidylcholine breakdown in fibroblasts via activation of phospholipase D. Comparison with the response to endothelin

Abstract

Lysophosphatidic acid (LPA) is a simple phospholipid that possesses hormone- and growth-factor-like properties. LPA initiates its action by inducing GTP-dependent phosphoinositide hydrolysis and inhibiting adenylate cyclase [van Corven, Groenink, Jalink, Eichholtz & Moolenaar (1989) Cell 59, 45-54]. Here we show that LPA stimulates rapid breakdown of phosphatidylcholine (PC) in Rat-1 fibroblasts. LPA-induced PC breakdown occurs through activation of phospholipase D (PLD), as measured by the formation of free choline and phosphatidic acid and by transphosphatidylation in the presence of butan-1-ol. LPA also stimulates generation of diacylglycerol, but there is no detectable formation of phosphocholine, suggesting that a PC-specific phospholipase C (PLC) is not involved. The response to LPA was compared with that to endothelin, a potent inducer of phospholipid hydrolysis but a poor mitogen for Rat-1 cells. Our results indicate that: (1) LPA is less efficient than endothelin in inducing phosphoinositide and PC breakdown; (2) LPA-induced PLD activation is short-lived, levelling off after 2 min, whereas the endothelin-stimulated increase in PLD activity persists for at least 1 h; (3) the effect of LPA on PLD, like that of endothelin, is blocked by long-term pretreatment of the cells with phorbol ester, suggesting that PLD activation occurs through a protein kinase C-dependent mechanism. Furthermore, our results support the notion that there is no simple causal relationship between the degree of agonist-induced phospholipid hydrolysis and the magnitude of the mitogenic response.

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

“…Certainly early reports implicating exogenous PA in intracellular Ca 2ϩ release are clearly attributable to LPA contamination (165). Small amounts of LPA with PA likely explain effects on arachidonate release (172,256) and PC-PLD activation (80,257). These effects are attributable to LPA receptor interactions.…”

Lysophosphatidic acid inhibits gap-junctional communication and stimulates phosphorylation of connexin-43 in WB cells: possible involvement of the mitogen-activated protein kinase cascade

“…Binding of LPA to this protein was inhibited by suramin, a polysulphonated naphthylurea derivative that also blocks the biological response of intact cells to LPA [7]. The initiating events in LPA-induced mitogenesis are not established, but rapid responses include inhibition of G-protein-linked adenylate cyclase [3], activation of both inositol lipid hydrolysis by phospholipase C [8] and phosphatidylcholine hydrolysis by phospholipase D [9], and activation of p2Iras [10]. In addition, LPA has been shown to modulate the assembly of actin stress fibres via the GTP-binding protein rho [11].…”

LPA4/GPR23 Is a Lysophosphatidic Acid (LPA) Receptor Utilizing Gs-, Gq/Gi-mediated Calcium Signaling and G12/13-mediated Rho Activation

“…LPA 4 is the only receptor that has yet to receive independent confirmation as a bona fide LPA receptor since its initial report (20). This putative LPA receptor was remarkable for its relatively low predicted amino acid sequence homology compared with the well studied LPA 1-3 , a K d ϳ45 nM for LPA, and an ability to mobilize calcium and increase cAMP production (20).…”

“…Five LPA-specific GPCRs have thus far been identified, termed LPA [1][2][3][4][5] (17)(18)(19)(20)(21)(22). LPA 4 is the only receptor that has yet to receive independent confirmation as a bona fide LPA receptor since its initial report (20).…”

“…Lysophosphatidic acid (LPA, 2 1-acyl-2-sn-glycerol-3-phosphate) is a water-soluble bioactive phospholipid that can be generated by many cell types and has been shown to influence multiple intracellular signaling pathways, including stimulation of phospholipase C and D, activation of small GTPases, MAPK (mitogen-activated protein kinase), and phosphoinositide 3-kinase (1,2), and inhibition of adenylyl cyclase (3,4). LPA signaling through G proteins mediates a variety of biological functions, including cell proliferation, cell survival, cytoskeletal remodeling, cell migration, and alterations in differentiation (3,(5)(6)(7)(8)(9).…”