title: Amitriptyline induces early growth response-1 gene expression via ERK and JNK mitogen-activated protein kinase pathways in rat C6 glial cells.
abstract: Astrocytes play important roles in guiding the construction of the nervous system, controlling extracellular ions and neurotransmitters, and regulating CNS synaptogenesis. Egr-1 is a transcription factor involved in neuronal differentiation and astrocyte cell proliferation. In this study, we investigated whether the tricyclic antidepressant (TCA) amitriptyline induces Egr-1 expression in astrocytes using rat C6 glioma cells as a model. We found that amitriptyline increased the expression of Egr-1 in a dose- and time-dependent manner. The amitriptyline-induced Egr-1 expression was mediated through serum response elements (SREs) in the Egr-1 promoter. SREs were activated by the Ets-domain transcription factor Elk-1 through the ERK and JNK mitogen-activated protein (MAP) kinase pathways. The inhibition of the ERK and JNK MAP kinase signals attenuated amitriptyline-induced transactivation of Gal4-Elk-1 and Egr-1 promoter activity. Our findings suggest that the induction of Egr-1 expression in astrocytes may be required to attain the therapeutic effects of antidepressant drugs.
authors.affiliation: Institute of Molecular Life Science and Technology, Ewha Women's University, Seoul 120-750, South Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Chung
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000502:physiology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D051766:Early Growth Response Protein 1; D050807:ets-Domain Protein Elk-1; D000639:Amitriptyline; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases