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

Abstract

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.

Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special?

“…Taken together, these studies suggested that complex positive and negative interactions exist between LPARs, other GPCRs, and EGFR that cannot be easily explained by activation of downstream signaling pathways. Meizoso and colleagues [179] pursued this idea, showing that FFAR4 functionally desensitizes LPAR1. Importantly, they provided evidence that FFAR4 agonists induce a physical interaction between FFAR4 and LPAR2.…”

Phosphoproteomics Reveals Selective Regulation of Signaling Pathways by Lysophosphatidic Acid Species in Macrophages

“…It is plausible that interacting molecules or protein modifications could exert cell-type-specific influences on receptor functionality. This is exemplified by free fatty acid receptor 4 (FFA4), which can functionally desensitize LPAR1 [68]. While these questions lie beyond the immediate scope of our study, they warrant future investigation in the context of LPA signaling in OC.…”

BRET analysis reveals interaction between the lysophosphatidic acid receptor LPA2 and the lysophosphatidylinositol receptor GPR55 in live cells

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