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

Lysophosphatidic acid (LPA) and lysophosphatidylinositol bind to the G protein-coupled receptors (GPCRs) LPA and GPR55, respectively. LPA , a type 2 LPA receptor, and GPR55 are highly expressed in colon cancer and involved in cancer progression. However, crosstalk between the two receptors and potential effects on cellular physiology are not fully understood. Here, using BRET analysis, we found that LPA and GPR55 interact in live cells. In the presence of both receptors, LPA and/or GPR55 activation facilitated co-internalization, and activation of GPR55, uncoupled with Gα , induced reduction of intracellular cAMP. Notably, co-activation of receptors synergistically triggered further decline in the cAMP level, promoted cell proliferation, and increased the expression of cancer progression-related genes, suggesting that physical and functional crosstalk between LPA and GRR55 is involved in cancer progression.