Regulation of LPA receptor function by estrogens

17β-Estradiol induced LPA1 receptor desensitization in C9 cells stably expressing LPA1 receptors and transiently expressing estrogen receptor α. Such desensitization was evidenced by a reduction in lysophosphatidic acid-mediated Ca2+mobilization and it was associated to receptor phosphorylation and internalization. These effects of 17β-estradiol were rapid (taking place over 5 min) and were blocked by the estrogen receptor antagonist ICI 182780. Similarly, inhibitors of phosphoinositide 3-kinase (wortmannin and LY294002) and of protein kinase C (staurosporine and Gö 6976) blocked 17β-estradiol-induced LPA1 receptor desensitization and phosphorylation. Confocal microscopy evidenced LPA1 receptor internalization in response to 17β-estradiol treatment. Association between LPA1 receptors and protein kinase C α was suggested by co-immunoprecipitation assays. Protein kinase C α was associated with LPA1 receptors in the absence of stimulus and such association further increased in a dynamic fashion in response to 17β-estradiol. The results demonstrated that in C9 cells estrogens modulate LPA1 action through estrogen receptor α with the participation of protein kinase C α and phosphoinositide 3-kinase.