Differential targeting of lysophosphatidic acid LPA, LPA, and LPA receptor signalling by tricyclic and tetracyclic antidepressants.

We previously reported that in different cell types antidepressant drugs activate lysophosphatidic acid (LPA) LPA 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, LPA and LPA. Human LPA receptors were stably expressed in HEK-293 cells (HEK-LPA, -LPA and -LPA 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-LPA, -LPA, and -LPA cells. The tricyclic antidepressants amitriptyline, clomipramine, imipramine and desipramine increased phospho-ERK1/2 levels in HEK-LPA and -LPA cells but were relatively poor agonists in LPA-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-mediated phosphorylation of ERK1/2 induced by LPA in HEK-LPA, -LPA and -LPA 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-mediated phosphorylation of AMP-activated protein kinase in HEK-LPA and -LPA cells. Conversely, amitriptyline and mianserin were found to inhibit LPA-induced Rho activation in HEK-LPA and LPA cells. These results indicate that tricyclic and tetracyclic antidepressants can act on LPA, LPA and LPA receptor subtypes and exert differential effects on LPA signalling through these receptors.