Back to Search
Start Over
Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation.
- Source :
-
Psychopharmacology . Dec2008, Vol. 201 Issue 3, p443-458. 16p. 1 Chart, 13 Graphs. - Publication Year :
- 2008
-
Abstract
- Fluoxetine has relatively high affinity for Gq/11 protein-coupled 5-HT2 receptors. Part of these receptors in brain are on astrocytes, where fluoxetine causes an increase in free cytosolic calcium concentration ([Ca2+]i) and phosphorylation of extracellular regulated kinase 1 and 2 (ERK1/2). The objectives of the study are to identify subtype of the 5-HT2 receptor involved, to establish whether ERK1/2 phosphorylation is a result of 5-HT2-mediated transactivation of epidermal growth factor (EGF) receptors (EGFRs), and to determine signaling pathways up- and downstream of ERK1/2. Primary cultures of mouse astrocytes, which express all three subtypes of the 5-HT2 receptor but no 5-HT2 transporter, were used. ERK1/2 phosphorylation and c-Fos and FosB protein expression were determined with Western blotting, and c-fos and fosB mRNA expression with reverse transcription polymerase chain reaction. Receptor subtype was investigated with subtype-specific 5-HT antagonists and 5-HT2B receptor depletion and signaling pathways by EGFR phosphorylation, using immunoprecipitation and Western blotting, inhibition of protein kinase C (PKC), and [Ca2+]i chelation by BAPTA/AM. ERK1/2 phosphorylation was abolished by SB204741, a universal 5-HT2 receptor antagonist, and in 5-HT2B receptor-depleted cells, but unaffected by 5-HT2A or 5-HT2C receptor antagonists (M100907 and SB242084). Phosphorylation of ERK1/2 and EGFRs was abolished by AG 1478, an inhibitor of EGFR tyrosine kinases, and GM 6001, an inhibitor of Zn-dependent metalloproteinases, suggesting growth factor “shedding” and transactivation of EGFRs. Chelation of [Ca2+]i or PKC inhibition with GF 109203X abrogated ERK1/2 phosphorylation. Up-regulated mRNA and protein expression of c-fos and fosB was abolished by SB204741, AG1478, and by U0126, an inhibitor of ERK phosphorylation by MAP kinase/ERK kinase. [ABSTRACT FROM AUTHOR]
- Subjects :
- *FLUOXETINE
*ASTROCYTES
*PHOSPHORYLATION
*SEROTONIN
*POLYMERASE chain reaction
Subjects
Details
- Language :
- English
- ISSN :
- 00333158
- Volume :
- 201
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Psychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 35277404
- Full Text :
- https://doi.org/10.1007/s00213-008-1306-5