LPA1 Mediates Antidepressant-Induced ERK1/2 Signaling and Protection from Oxidative Stress in Glial Cells.
Antidepressants have been shown to affect glial cell functions and intracellular signaling through mechanisms that are still not completely understood. In the present study, we provide evidence that in glial cells the lysophosphatidic acid (LPA) receptor LPA1mediates antidepressant-induced growth factor receptor transactivation, ERK1/2 signaling, and protection from oxidative stress. Thus, in C6 glioma cells and rat cortical astrocytes, ERK1/2 activation induced by either amitriptyline or mianserin was antagonized by Ki16425 and VPC 12249 (S), which block LPA1and LPA3receptors, and by AM966, which selectively blocks LPA1Cell depletion of LPA1with siRNA treatment markedly reduced antidepressant- and LPA-induced ERK1/2 phosphorylation. LPA1blockade prevented antidepressant-induced phosphorylation of the transcription factors CREB and Elk-1. Antidepressants and LPA signaling to ERK1/2 was abrogated by cell treatment with pertussis toxin and by the inhibition of fibroblast growth factor (FGF) receptor (FGF-R) and platelet-derived growth factor receptor (PDGF-R) tyrosine kinases. Both Ki16425 and AM966 suppressed antidepressant-induced phosphorylation of FGF-R. Moreover, blockade of LPA1or inhibition of FGF-R and PDGF-R activities prevented antidepressant-stimulated Akt and GSK-3β phosphorylations. Mianserin protected C6 glioma cells and astrocytes from apoptotic cell death induced by H2O2, as indicated by increased cell viability, decreased expression of cleaved caspase 3, reduced cleavage of poly-ADP ribose polymerase and inhibition of DNA fragmentation. The protective effects of mianserin were antagonized by AM966. These data indicate that LPA1constitutes a novel molecular target of the regulatory actions of tricyclic and tetracyclic antidepressants in glial cells.
Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy (M.C.O., S.D., P.O.).
Maria C
MC
Olianas
Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy (M.C.O., S.D., P.O.).
Simona
S
Dedoni
Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy (M.C.O., S.D., P.O.) onali@unica.it.
Pierluigi
P
Onali
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008246:Lysophospholipids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008803:Mianserin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D037342:Pertussis Toxin / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D000928:Antidepressive Agents; D017362:Cyclic AMP Response Element-Binding Protein; D008246:Lysophospholipids; D017468:Receptors, Fibroblast Growth Factor; D049368:Receptors, Lysophosphatidic Acid; D050807:ets-Domain Protein Elk-1; D000639:Amitriptyline; D008803:Mianserin; D037342:Pertussis Toxin; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C032881:lysophosphatidic acid