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Vol. 54, Issue 6, 979-988, December 1998
Department of Physiology and Biophysics (D.J.F., K.L., Z.G., N.N.,
T.V., G.T.) and
Department of Pharmaceutical Sciences (G.S., D.D.M.),
The University of Tennessee, Memphis, TN 38163, Department of Biology,
Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112, Japan
(K.M.-M.),
Faculty of Pharmaceutical Sciences, Science University of
Tokyo, Shinjuku-ku, Tokyo 162, Japan (S.K.),
LXR Biotechnology Inc.,
Richmond, CA 94804 (J.R.E.), and
Institute of Enzymology, Biological
Research Center of the Hungarian Academy of Sciences, Budapest, 1501, Hungary (K.L.)
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.
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