LPA1 is a key mediator of intracellular signalling and neuroprotection triggered by tetracyclic antidepressants in hippocampal neurons

• Published in: Journal of neurochemistry 2017-10, Vol.143 (2), p.183-197
• Main Authors: Olianas, Maria C., Dedoni, Simona, Onali, Pierluigi
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Annexin V; Antidepressants; Apoptosis; Caspase; Cyclic AMP; Cyclic AMP response element-binding protein; Differentiation; Down-regulation; ERK1/2 signalling; Extracellular signal-regulated kinase; Fibroblast growth factors; hippocampal neurons; Hippocampus; Intracellular; Intracellular signalling; Kinases; LPA receptors; Lysophosphatidic acid; Mianserin; Neurons; Neuroprotection; Overexpression; Pertussis; Pertussis toxin; Phosphorylation; Proteins; Receptors; Ribose; Rodents; siRNA; Stimulation; Survival; tetracyclic antidepressants; Tyrosine
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14150

Both lysophosphatidic acid (LPA) and antidepressants have been shown to affect neuronal survival and differentiation, but whether LPA signalling participates in the action of antidepressants is still unknown. In this study, we examined the role of LPA receptors in the regulation of extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) activity and neuronal survival by the tetracyclic antidepressants, mianserin and mirtazapine in hippocampal neurons. In HT22 immortalized hippocampal cells, antidepressants and LPA induced a time‐ and concentration‐dependent stimulation of ERK1/2 phosphorylation. This response was inhibited by either LPA1 and LPA1/3 selective antagonists or siRNA‐induced LPA1 down‐regulation, and enhanced by LPA1 over‐expression. Conversely, the selective LPA2 antagonist H2L5186303 had no effect. Antidepressants induced cyclic AMP response element binding protein phosphorylation and this response was prevented by LPA1 blockade. ERK1/2 stimulation involved pertussis toxin‐sensitive G proteins, Src tyrosine kinases and fibroblast growth factor receptor (FGF‐R) activity. Tyrosine phosphorylation of FGF‐R was enhanced by antidepressants through LPA1. Serum withdrawal induced apoptotic death, as indicated by increased annexin V staining, caspase activation and cleavage of poly‐ADP‐ribose polymerase. Antidepressants inhibited the apoptotic cascade and this protective effect was curtailed by blockade of either LPA1, ERK1/2 or FGF‐R activity. Moreover, in primary mouse hippocampal neurons, mianserin acting through LPA1 increased phospho‐ERK1/2 and protected from apoptosis induced by removal of growth supplement. These data indicate that in neurons endogenously expressed LPA1 receptors mediate intracellular signalling and neuroprotection by tetracyclic antidepressants. We show that in HT22 immortalized hippocampal cells and primary hippocampal neurons, the tetracyclic antidepressants, mianserin and mirtazapine trigger ERK1/2 phosphorylation and protect from apoptosis induced by removal of growth supplement through activation of the lysophosphatidic acid receptor LPA1. In HT22 cells, antidepressant‐activated LPA1 up‐regulates fibroblast growth factor receptor activity to induce pro‐survival signalling via ERK1/2 and CREB. The data indicate that LPA1 is a critical component of tetracyclic antidepressant‐induced neuroprotection.