Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes

David J. Fischer, Károly Liliom, Zhong Guo, Nóra Nusser, Tamás Virág, Kimiko Murakami-Murofushi, Susumu Kobayashi, James R. Erickson, Guoping Sun, Duane Miller, Gabor Tigyi

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Abstract

Lysophosphatidic acid (LPA), plasmalogen-glycerophosphate (alkenyl-GP) and, cyclic-phosphatidic acid (cyclic-PA) are naturally occurring phospholipid growth factors (PLGFs). PLGFs elicit diverse biological effects via the activation of G protein-coupled receptors in a variety of cell types. In NIH3T3 fibroblasts, LPA and alkenyl-GP both induced proliferation, whereas cyclic-PA was antiproliferative. LPA and alkenyl-GP decreased cAMP in a pertussis toxin-sensitive manner, whereas cyclic-PA caused cAMP to increase. LPA and alkenyl-GP both stimulated the activity of the mitogen-actived protein kinases extracellular signal regulated kinases 1 and 2 and c-Jun NH2-terminal kinase, whereas cyclic-PA did not. All three PLGFs induced the formation of stress fibers in NIH3T3 fibroblasts. To determine whether these lipids activated the same or different receptors, heterologous desensitization patterns were established among the three PLGFs by monitoring changes in intracellular Ca2+ in NIH3T3 fibroblasts. LPA cross-desensitized both the alkenyl-GP and cyclic-PA responses. Alkenyl-GP cross-desensitized the cyclic-PA response, but only partially desensitized the LPA response. Cyclic-PA only partially desensitized both the alkenyl-GP and LPA responses. We propose that pharmacologically distinct subsets of PLGF receptors exist that distinguish between cyclic-PA and alkenyl-GP, but are all activated by LPA. We provide evidence that the PSP24 receptor is selective for LPA and not activated by the other two PLGFs. RT-PCR and Northern blot analysis indicate the co-expression of mRNAs encoding the EDG-2, EDG-4, and PSP24 receptors in a variety of cell lines and tissues. However, the lack of mRNA expression for these three receptors in the LPA-responsive Rat-1 and Sp2-O-Ag14 cells suggests that a number of PLGF receptor subtypes remain unidentified.

Original languageEnglish (US)
Pages (from-to)979-988
Number of pages10
JournalMolecular Pharmacology
Volume54
Issue number6
DOIs
StatePublished - Jan 1 1998

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Phosphatidic Acids
Phospholipids
Intercellular Signaling Peptides and Proteins
Growth Factor Receptors
Fibroblasts
Lysophosphatidic Acid Receptors
Plasmalogens
Glycerophosphates
lysophosphatidic acid
Stress Fibers
Messenger RNA
Mitogen-Activated Protein Kinase 3
1-O-cis-alk-1'-enyl-2-lyso-sn-glycero-3-phosphate
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Pertussis Toxin
G-Protein-Coupled Receptors
Mitogens
Northern Blotting
Protein Kinases

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes. / Fischer, David J.; Liliom, Károly; Guo, Zhong; Nusser, Nóra; Virág, Tamás; Murakami-Murofushi, Kimiko; Kobayashi, Susumu; Erickson, James R.; Sun, Guoping; Miller, Duane; Tigyi, Gabor.

In: Molecular Pharmacology, Vol. 54, No. 6, 01.01.1998, p. 979-988.

Research output: Contribution to journalArticle

Fischer, DJ, Liliom, K, Guo, Z, Nusser, N, Virág, T, Murakami-Murofushi, K, Kobayashi, S, Erickson, JR, Sun, G, Miller, D & Tigyi, G 1998, 'Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes', Molecular Pharmacology, vol. 54, no. 6, pp. 979-988. https://doi.org/10.1124/mol.54.6.979
Fischer, David J. ; Liliom, Károly ; Guo, Zhong ; Nusser, Nóra ; Virág, Tamás ; Murakami-Murofushi, Kimiko ; Kobayashi, Susumu ; Erickson, James R. ; Sun, Guoping ; Miller, Duane ; Tigyi, Gabor. / Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes. In: Molecular Pharmacology. 1998 ; Vol. 54, No. 6. pp. 979-988.
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AU - Virág, Tamás

AU - Murakami-Murofushi, Kimiko

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