Differential targeting of lysophosphatidic acid LPA 1 , LPA 2 , and LPA 3 receptor signalling by tricyclic and tetracyclic antidepressants.

Autor: Olianas MC; Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, (CA), Italy., Dedoni S; Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, (CA), Italy., Onali P; Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, (CA), Italy. Electronic address: onali@unica.it.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2023 Nov 15; Vol. 959, pp. 176064. Date of Electronic Publication: 2023 Sep 25.
DOI: 10.1016/j.ejphar.2023.176064
Abstrakt: We previously reported that in different cell types antidepressant drugs activate lysophosphatidic acid (LPA) LPA 1 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 2 and LPA 3 . Human LPA 1-3 receptors were stably expressed in HEK-293 cells (HEK-LPA 1 , -LPA 2 and -LPA 3 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 1 , -LPA 2 , and -LPA 3 cells. The tricyclic antidepressants amitriptyline, clomipramine, imipramine and desipramine increased phospho-ERK1/2 levels in HEK-LPA 1 and -LPA 3 cells but were relatively poor agonists in LPA 2 -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-LPA 1 , -LPA 2 and -LPA 3 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-LPA 1 and -LPA 3 cells. Conversely, amitriptyline and mianserin were found to inhibit LPA-induced Rho activation in HEK-LPA 1 and LPA 2 cells. These results indicate that tricyclic and tetracyclic antidepressants can act on LPA 1 , LPA 2 and LPA 3 receptor subtypes and exert differential effects on LPA signalling through these receptors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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