MOLECULAR-CLONING OF A HIGH-AFFINITY RECEPTOR FOR THE GROWTH FACTOR-LIKE LIPID MEDIATOR LYSOPHOSPHATIDIC ACID FROM XENOPUS OOCYTES

Lysophosphatidic acid (1-acyl-2-lyso-sn-glycero-3-phosphate, LPA) is a multifunctional lipid mediator found in a variety of organisms that s pan the phylogenetic tree from humans to plants, Although its physiolo gical function is not clearly understood, LPA is a potent regulator of mammalian cell proliferation; it is one of the major mitogens found i n blood serum, In Xenopus laevis oocytes, LPA elicits oscillatory Cl- currents. This current, like other effects of LPA, is consistent with a plasma membrane receptor-mediated activation of G protein-linked sig nal transduction pathways, Herein we report the identification of a co mplementary DNA from Xenopus that encodes a functional high-affinity L PA receptor, The predicted structure of this protein of 372 amino acid s contains features common to members of the seven transmembrane recep tor superfamily with a predicted extracellular amino and intracellular carboxyl terminus, An antisense oligonucleotide derived from the firs t 5-11 predicted amino acids, selectively inhibited the expression of the endogenous high-affinity LPA receptors in Xenopus oocytes, whereas the same oligonucleotide did not affect the low-affinity LPA receptor , Expression of the full-length cRNA in oocytes led to an increase in maximal Cl- current due to increased expression of the high-affinity L PA receptor, but activation of the low-affinity receptor was, again, u naffected, Oocytes expressing cRNA prepared from this clone showed no response to other lipid mediators including prostaglandins, leukotrien es, sphingosine 1-phosphate, sphingosylphosphorylcholine, and platelet -activating factor, suggesting that the receptor is highly selective f or LPA.