CHARACTERIZATION OF A NOVEL SUBTYPE OF HUMAN G-PROTEIN-COUPLED RECEPTOR FOR LYSOPHOSPHATIDIC ACID

The recent identification of the Vzg-1/Edg2 protein as a functional G protein coupled receptor for lysophosphatidic acid (LPA) has allowed a sequence based search for new ones that may encode novel subtypes of LPA receptors. A human cDNA encoding a G protein-coupled receptor, des ignated Edg4, was identified by searching the GenBank(TM) for homologs of the human Ed2 LPA receptor. The Edg4 protein is 46% identical and 72% similar in amino acid sequence to human Edg2. When overexpressed i n Jurkat T cells, the Edg4 protein mediated LPA-induced activation of a serum response element reporter gene with LPR concentration dependen ce (EC50 of 10 nM) and specificity, This LPA-induced reporter gene act ivation could be partially inhibited by pretreatment with petussis tox in or C3 exoenzyme, suggesting requirements for both a G(i) protein an d Rho GTPase. Overexpression of Edg4 in Jurkat cells also led to incre ases in specific binding sites for [H-3]LPA. Northern blots revealed t hat two edg4 mRNA transcripts of 1.8 and 8 kilobases are distributed v ery differently from edg2 nRNAs in adult human tissues and several can cer cell lines. The existence and distinctive tissue expression of str ucturally different subtypes of LPA receptors may provide one basis fo r tissue-specific functions and permit independent regulation of each subtype of LPA receptor.