N-palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids are selective competitive antagonists of the lysophosphatidic acid receptors

K. Liliom, Robert Bittman, Bernadette Swords, Gabor Tigyi

Research output: Contribution to journalArticle

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Abstract

Lysophosphatidic acid is the best characterized member of a lipid mediator family with growth factor-like activities that act through a class of G protein-coupled plasma membrane receptors. In Xenopus laevis oocytes, lysophosphatidate activates at least two pharmacologically distinct receptor subtypes distinguished by 1-acyl-sn-glycero-2,3-cyclic phosphate. Both of these naturally occurring ligands elicit oscillatory Cl- currents in the oocyte through G protein-coupled activation of the phosphoinositide/Ca2+ second messenger system, which in turn leads to the opening of Ca2+- activated Cl- channels. We developed an improved chemical synthesis and purification procedure for two N-acylated amino acid phosphates. N- Palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids inhibited the lysophosphatidate-activated Cl- currents with IC50 values of 5.4 ± 0.7 and 6.5 ± 1.5 nM at the high affinity site and 805 ± 97 and 172 ± 36 nM at the low affinity receptor site, respectively. In selective activation of the cyclic lysophosphatidate receptor, IC50 values of 330 ± 30 and 490 ± 40 nM were obtained, respectively. The D- and L-stereoisomers were equally effective when applied extracellularly. In contrast, they were ineffective when microinjected into the oocyte, indicating an extracellular site of inhibition. The inhibitors did not alter currents elicited by the different acetylcholine, serotonin, and glutamate receptors expressed heterologously in the oocyte. Pharmacological analysis of the results indicates that N- palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids are potent and specific competitive inhibitors of the lysophosphatidate receptors in the X. laevis oocyte.

Original languageEnglish
Pages (from-to)616-623
Number of pages8
JournalMolecular Pharmacology
Volume50
Issue number3
Publication statusPublished - Sep 1996

Fingerprint

Lysophosphatidic Acid Receptors
Serine
Oocytes
Xenopus laevis
GTP-Binding Proteins
Inhibitory Concentration 50
Phosphates
Stereoisomerism
Serotonin Receptors
Glutamate Receptors
Second Messenger Systems
Cholinergic Receptors
Phosphatidylinositols
Intercellular Signaling Peptides and Proteins
Cell Membrane
N-palmitoyltyrosine phosphoric acid
Pharmacology
Ligands
Lipids
Amino Acids

ASJC Scopus subject areas

  • Pharmacology

Cite this

N-palmitoyl-serine and N-palmitoyl-tyrosine phosphoric acids are selective competitive antagonists of the lysophosphatidic acid receptors. / Liliom, K.; Bittman, Robert; Swords, Bernadette; Tigyi, Gabor.

In: Molecular Pharmacology, Vol. 50, No. 3, 09.1996, p. 616-623.

Research output: Contribution to journalArticle

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