Differential targeting of lysophosphatidic acid LPA1, LPA2, and LPA3 receptor signalling by tricyclic and tetracyclic antidepressants

Abstract

We previously reported that in different cell types antidepressant drugs activate lysophosphatidic acid (LPA) LPA₁ receptor to induce proliferative and prosurvival responses. Here, we further characterize this unique action of antidepressants by examining their effects on two additional LPA receptor family members, LPA₂ and LPA₃. Human LPA_1-3 receptors were stably expressed in HEK-293 cells (HEK-LPA₁, -LPA₂ and -LPA₃ cells) and their functional activity was determined by Western blot and immunofluorescence. LPA effectively stimulated the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in HEK-LPA₁, -LPA₂, and -LPA₃ cells. The tricyclic antidepressants amitriptyline, clomipramine, imipramine and desipramine increased phospho-ERK1/2 levels in HEK-LPA₁ and -LPA₃ cells but were relatively poor agonists in LPA₂-expressing cells. The tetracyclic antidepressants mianserin and mirtazapine were active at all three LPA receptors. When combined with LPA, both amitriptyline and mianserin potentiated G_i/o-mediated phosphorylation of ERK1/2 induced by LPA in HEK-LPA₁, -LPA₂ and -LPA₃ cells, CHO-K1 fibroblasts and HT22 hippocampal neuroblasts. This potentiation was associated with enhanced phosphorylation of CREB and S6 ribosomal protein, two molecular targets of activated ERK1/2. The antidepressants also potentiated LPA-induced G_q/11-mediated phosphorylation of AMP-activated protein kinase in HEK-LPA₁ and -LPA₃ cells. Conversely, amitriptyline and mianserin were found to inhibit LPA-induced Rho activation in HEK-LPA₁ and LPA₂ cells. These results indicate that tricyclic and tetracyclic antidepressants can act on LPA₁, LPA₂ and LPA₃ receptor subtypes and exert differential effects on LPA signalling through these receptors.

Keywords: Antidepressants; HEK-293 cells; Human LPA receptors; Receptor signalling.