Free fatty acid receptor 4 agonists induce lysophosphatidic acid receptor 1 (LPA1 ) desensitization independent of LPA1 internalization and heterodimerization.

The crosstalk between the free fatty acid receptor FFA4 and the lysophosphatidic acid receptor LPA1 seems to be of pathophysiological importance. We explored this crosstalk employing co-expression of fluorescent protein-tagged receptors. FFA4 activation induces functional desensitization of LPA1 receptors and phosphorylation of both receptors. LPA1 activation induces phosphorylation of LPA1 , but not of FFA4, and induces internalization of both receptors into heterogeneous types of vesicles. Docosahexaenoic acid (DHA) induces internalization of FFA4 but not of LPA1 . Fatty acid-induced FFA4-LPA1 interaction was observed using Förster resonance energy transfer and co-immunoprecipitation. Such interaction took place after desensitization was already established. Data indicate that FFA4 activation induces LPA1 desensitization in an internalization-independent process and that complex cellular processes participate in the crosstalk of these receptors.