Antidepressants activate the lysophosphatidic acid receptor LPA(1) to induce insulin-like growth factor-I receptor transactivation, stimulation of ERK1/2 signaling and cell proliferation in CHO-K1 fibroblasts

作者：Olianas Maria C; Dedoni Simona; Onali Pierluigi^*

来源：Biochemical Pharmacology, 2015, 95(4): 311-323.

DOI：10.1016/j.bcp.2015.04.002

• Antidepressants
• LPA(1) receptor
• ERK1/2
• Insulin-like growth factor-I receptor
• CHO-K1 fibroblasts

Different lines of evidence indicate that the lysophosphatidic acid (LPA) receptor LPA(1) is involved in neurogenesis, synaptic plasticity and anxiety-related behavior, but little is known on whether this receptor can be targeted by neuropsychopharmacological agents. The present study investigated the effects of different antidepressants on LPA(1) signaling. We found that in Chinese hamster ovary (CHO)-K1 fibroblasts expressing endogenous LPA(1) tricyclic and tetracyclic antidepressants and fluoxetine induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and CREB. This response was antagonized by either LPA(1) blockade with Ki16425 and AM966 or knocking down LPA(1) with siRNA. Antidepressants induced ERK1/2 phosphorylation in human embryonic kidney (HEK)-293 cells overexpressing LPA(1), but not in wild-type cells. In PathHunter (TM) assay measuring receptor-P-arrestin interaction, amitriptyline, mianserin and fluoxetine failed to induce activation of LPA(2) and LPA(3) stably expressed in CHO-K1 cells. ERK1/2 stimulation by antidepressants and LPA was suppressed by pertussis toxin and inhibition of Src, phosphatidylinositol-3 kinase and insulin-like growth factor-I receptor (IGF-IR) activities. Antidepressants and LPA induced tyrosine phosphorylation of IGF-IR and insulin receptor-substrate-1 through LPA(1) and Src. Prolonged exposure of CHO-K1 fibroblasts to either mianserin, mirtazapine or LPA enhanced cell proliferation as indicated by increased [H-3]-thymidine incorporation and Ki-67 immunofluorescence. This effect was inhibited by blockade of LPA(1), - and ERK1/2 activity. These data provide evidence that different antidepressants induce LPA(1) activation, leading to receptor tyrosine kinase transactivation, stimulation of ERK1/2 signaling and enhanced cell proliferation.

• 出版日期2015-6-15