Abstract
LPA and sphingosine-1-phosphate (S1P) are two major natural bioactive lysophospholipids that induce a wide variety of biological responses mainly via the endothelial differentiation gene (Edg) G protein-coupled receptor family in diverse cell types. Among the Edg family, Edg-1, -3, -5, -6, and -8 (S1P1–S1P5) are S1P-specific receptors, and Edg-2, -4, and -7 (LPA1–LPA3) are LPA-specific receptors. We previously demonstrated in CHO cells that S1P1/Edg1 and S1P3/Edg3 mediated stimulation of Rac and chemotaxis, whereas S1P2/Edg5 mediated inhibition of a chemoattractant-induced Rac stimulation and chemotaxis. S1P2 mediated Rho stimulation via G12/13, and Rho in turn mediated inhibition of Rac and cell migration. Complexly, S1P3 stimulated Rac and cell migration despite stimulating Rho. Like S1P3, LPA1/Edg2, stimulated both Rho and Rac with stimulation of cell migration. The stimulatory effects of both LPA1 and S1P3 on Rac and cell migration and Rho are mediated by Gi and G12/13, respectively. Either Rho inactivation by C3 toxin or inhibition of G12/13 enhanced LPA1-mediated stimulation of Rac and cell migration. On the other hand, Gi inactivation by pertussis toxin abolished LPA1-mediated induced Rac stimulation and cell migration, and induced LPA1-mediated inhibition of IGF I-induced Rac activation and chemotaxis. These LPA1-mediated responses were very similar to S1P3-mediated responses in PTX-treated CHO cells. Thus, LPA1 generates stimulatory and inhibitory signals via Gi and G12/13-Rho, which are counteracting with each other, just like S1P3. [Jpn J Physiol 55 Suppl:S76 (2005)]
