Amitriptyline induces early growth response-1 gene expression via ERK and JNK mitogen-activated protein kinase pathways in rat C6 glial cells.
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.
Chung
Eun Young
EY
Institute of Molecular Life Science and Technology, Ewha Women's University, Seoul 120-750, South Korea.
Shin
Soon Young
SY
Lee
Young Han
YH
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
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