The crosstalk between the free fatty acid receptor FFA4 and the lysophosphatidic acid receptor LPA seems to be of pathophysiological importance. We explored this crosstalk employing co-expression of fluorescent protein-tagged receptors. FFA4 activation induces functional desensitization of LPA receptors and phosphorylation of both receptors. LPA activation induces phosphorylation of LPA , 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 LPA . Fatty acid-induced FFA4-LPA 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 LPA desensitization in an internalization-independent process and that complex cellular processes participate in the crosstalk of these receptors.