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

Abstract

Lysophosphatidic acid (LPA) and lysophosphatidylinositol bind to the G protein-coupled receptors (GPCRs) LPA and GPR55, respectively. LPA 2 , 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 2 and GPR55 interact in live cells. In the presence of both receptors, LPA 2 and/or GPR55 activation facilitated co-internalization, and activation of GPR55, uncoupled with Ga i , 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 2 and GRR55 is involved in cancer progression.

Lysophosphatidylinositol Promotes Chemotaxis and Cytokine Synthesis in Mast Cells with Differential Participation of GPR55 and CB2 Receptors

“…The data suggest that, besides the actions of GPR55 and CB2 receptors alone, the formation of GPR55-CB2 dimers could participate in the expression of cytokine genes triggered by LPI. GPR55 receptor interaction with distinct GPCRs, such as the S1PR [ 43 ] and the lysophosphatidic acid (LPA) 2 receptor [ 44 ], has been demonstrated in some cell preparations. Specifically, GPR55 dimer formation with cannabinoid receptors has been previously observed in neutrophils, transfected HEK293 cells, and cancer cells [ 18 , 45 , 46 ].…”

Elucidation of GPR55-Associated Signaling behind THC and LPI Reducing Effects on Ki67-Immunoreactive Nuclei in Patient-Derived Glioblastoma Cells

“…It is known that GPR55 does not interact with Gα o/i proteins. Alternatively, GPR55 is able to form heterodimers with Gα o/i -coupled receptors, as described for CB 1 [45], CB 2 [46,47], and LPA2 [48], resulting in an altered activity and signal transduction of GPR55. To test the involvement of Gα o/i proteins, PTX was used, as it prevents signal transduction of Gα o/I by catalyzing irreversible ADP-ribosylation of the α subunit of trimeric Gα o/i βγ complexes [49].…”