Fluoxetine-induced transactivation of the platelet-derived growth factor type β receptor reveals a novel heterologous desensitization process
| Autor: | Jeff S. Kruk, Nawaz Ahmed, Michael A. Beazely, Maryam S. Vasefi, John J. Heikkila, Nyasha Gondora |
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| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Serotonin Biology Receptor tyrosine kinase Receptor Platelet-Derived Growth Factor beta Mice Cellular and Molecular Neuroscience Transactivation Cell Line Tumor Fluoxetine Enzyme-linked receptor Animals Humans Receptor Molecular Biology Cells Cultured G protein-coupled receptor Neurons Receptor transactivation Cell Biology Cell biology Cancer research biology.protein Receptors Serotonin 5-HT2 Serotonin 5-HT2 Receptor Agonists Selective Serotonin Reuptake Inhibitors Platelet-derived growth factor receptor |
| Zdroj: | Molecular and Cellular Neuroscience. 65:45-51 |
| ISSN: | 1044-7431 |
| DOI: | 10.1016/j.mcn.2015.02.013 |
| Popis: | Many G protein-coupled receptors (GPCRs), including serotonin (5-HT) receptors promote the activity of receptor tyrosine kinases (RTKs) via intracellular signaling pathways in a process termed transactivation. Although transactivation pathways are commonly initiated by a GPCR, a recent report demonstrated that serotonin-selective reuptake inhibitors (SSRIs) were able to block 5-HT-induced transactivation of the platelet-derived growth factor (PDGF) type β receptor. We show that a 45 min pretreatment of SH-SY5Y cells with the SSRI fluoxetine indeed blocked 5-HT-induced transactivation of the PDGFβ receptor. However, upon further examination, we discovered that during the pretreatment period, fluoxetine itself was transiently transactivating the PDGFβ receptor via 5-HT2 receptor activation. After 45 min, the increase in PDGFβ receptor phosphorylation induced by fluoxetine had returned to baseline, but a subsequent transactivating stimulus (5-HT) failed to “re-transactivate” the PDGFβ receptor. We further demonstrate that 45 min, but not 3 h, 5-HT pretreatment blocks dopamine-induced PDGFβ receptor transactivation. This did not involve changes in PDGF receptor function, since ligand (PDGF)-induced PDGFβ receptor activation was not inhibited by 5-HT pretreatment. To our knowledge this is the first demonstration of the heterologous desensitization of an RTK transactivation pathway and reveals a previously unknown short-term “blackout” period where no additional transactivation signaling is possible. |
| Databáze: | OpenAIRE |
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