Identification of Lysophosphatidic Acid Receptor 1 in Astroglial Cells as a Target for Glial Cell Line-derived Neurotrophic Factor Expression Induced by Antidepressants

Abstract

Preclinical and clinical evidence suggests that glial cell line-derived neurotrophic factor (GDNF) is important in the therapeutic effect of antidepressants. A previous study demonstrated that the tricyclic antidepressant amitriptyline induces Gα_i/o activation, which leads to GDNF expression in astrocytes. However, the specific target expressed in astrocytes that mediates antidepressant-evoked Gα_i/o activation has yet to be identified. Thus, the current study explored the possibility that antidepressant-induced Gα_i/o activation depends on lysophosphatidic acid receptor 1 (LPAR1), a Gα_i/o-coupled receptor. GDNF mRNA expression was examined using real-time PCR and Gα_i/o activation was examined using the cell-based receptor assay system CellKey^TM in rat C6 astroglial cells and rat primary cultured astrocytes. LPAR1 antagonists blocked GDNF mRNA expression and Gα_i/o activation evoked by various classes of antidepressants (amitriptyline, nortriptyline, mianserin, and fluoxetine). In addition, deletion of LPAR1 by RNAi suppressed amitriptyline-evoked GDNF mRNA expression. Treatment of astroglial cells with the endogenous LPAR agonist LPA increased GDNF mRNA expression through LPAR1, whereas treatment of primary cultured neurons with LPA failed to affect GDNF mRNA expression. Astrocytic GDNF expression evoked by either amitriptyline or LPA utilized, in part, transactivation of fibroblast growth factor receptor and a subsequent ERK cascade. The current results suggest that LPAR1 is a novel, specific target of antidepressants that leads to GDNF expression in astrocytes.

Keywords: G protein-coupled receptor (GPCR); antidepressants; astrocyte; depression; drug action; glial cell line-derived neurotrophic factor; lipid signaling; lysophosphatidic acid receptor 1; transactivation.