Premium
The Lysophosphatidic Acid LPA 1 Receptor as a Novel Molecular Target of Antidepressants in Neuronal Cells
Author(s) -
Olianas Maria C.,
Dedoni Simona,
Onali Pierluigi
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.929.1
Subject(s) - lysophosphatidic acid , creb , receptor , endocrinology , neuroprotection , medicine , pharmacology , microbiology and biotechnology , chemistry , biology , transcription factor , biochemistry , gene
Neuronal death and atrophy of brain limbic structures have been associated with stress and depression, and antidepressants have been reported to protect against neuronal cell loss induced by different neurotoxic insults. However, the molecular mechanisms mediating the neuroprotective effects of antidepressants have not been completely elucidated. Several studies have shown that the bioactive phospholipid lysophosphatidic acid (LPA) affects neurogenesis, synaptic plasticity and anxiety‐related behaviour through specific G‐protein coupled receptors, termed LPA 1–6 , which are expressed in the developing and adult brain. We have recently reported that different antidepressants induce growth factor receptor transactivation and cell proliferation in Chinese hamster ovary cells (Olianas et. al., Biochem. Pharmacol, 95, 311–323, 2015). In the present study, we show that in immortalized mouse hippocampal HT22 cells the tricyclic antidepressants amitriptyline and imipramine and the atypical antidepressants mianserin and mirtazapine trigger ERK1/2 phosphorylation and protect against apoptosis through the LPA 1 receptor. ERK1/2 phosphorylation induced by acute exposure to the antidepressants or LPA was inhibited by cell pre‐treatment with pertussis toxin, indicating the involvement of G proteins of the G i/o family. Antidepressants and LPA also promoted the phosphorylation of the transcription factor CREB, a downstream effector of ERK1/2 signaling. Cell treatment with either AM966, a selective LPA 1 receptor antagonist, or Ki16425, which preferentially blocks LPA 1 and LPA 3 receptors, significantly inhibited ERK1/2 and CREB phosphorylation elicited by the antidepressants. HT22 hippocampal cells underwent apoptosis following serum deprivation. Antidepressants and LPA markedly attenuated neuronal apoptosis, as indexed by increased cell viability, decreased percentage of annexin V‐positive cells, inhibition of pro‐caspase activation and poly‐(ADP ribose) polymerase cleavage. AM966 and Ki16425 reduced the protective effects of antidepressants and LPA against HT22 hippocampal cell apoptosis. These data demonstrate the involvement of the LPA 1 receptor in the neuroprotective action of different classes of antidepressants. Support or Funding Information The study was supported by Regione Autonoma della Sardegna, Italy, L.R. n. 7/2007‐CRP10810/2012.