RT Journal Article
SR Electronic
T1 Characterization of a Receptor Subtype-Selective Lysophosphatidic Acid Mimetic
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 188
OP 194
DO 10.1124/mol.53.2.188
VO 53
IS 2
A1 Shelley B. Hooks
A1 Seamus P. Ragan
A1 Darrin W. Hopper
A1 Christian W. Hönemann
A1 Marcel E. Durieux
A1 Timothy L. Macdonald
A1 Kevin R. Lynch
YR 1998
UL http://molpharm.aspetjournals.org/content/53/2/188.abstract
AB Despite an intriguing cell biology and the suggestion of a role in pathophysiological responses, the mechanism of action of such lipid phosphoric acid mediators as lysophosphatidic acid (LPA) remains obscure, in part because of an underdeveloped medicinal chemistry. We report now the agonist activity of a synthetic phospholipid in which the glycerol backbone of LPA is replaced by l-serine. Like LPA, the l-serine-based lipid mobilizes calcium and inhibits activation of adenylyl cyclase in the human breast cancer cell line MDA MB231. Treatment with LPA desensitizes MDA MB231 cells to subsequent application of the l-serine compound; when the order of application is reversed, however, the l-serine compound does not prevent calcium mobilization by LPA, which might indicate the existence of two LPA receptors in these cells. The analogous d-serine-based phospholipid was distinctly less potent than the l-isomer in those assays; this finding demonstrates stereoselectivity by an LPA receptor. Unlike LPA, thel-serine-based lipid does not evoke a chloride conductance in Xenopus laevis oocytes, but injection of poly(A)+ RNA from HEK 293 cells confers this phenotype on the oocyte. The latter result has practical importance in that it allows use of the frog oocyte for expression cloning of an LPA receptor DNA, an assay system made problematic by the oocyte’s strong endogenous response to LPA.