title: Fluoxetine-induced transactivation of the platelet-derived growth factor type β receptor reveals a novel heterologous desensitization process.
abstract: 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 45min, 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 45min, but not 3h, 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.
authors.affiliation: School of Pharmacy, University of Waterloo, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Kruk
authors.affiliation: School of Pharmacy, University of Waterloo, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada.
authors.forename: Maryam S
authors.initials: MS
authors.lastname: Vasefi
authors.affiliation: School of Pharmacy, University of Waterloo, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada.
authors.forename: Nyasha
authors.initials: N
authors.lastname: Gondora
authors.affiliation: School of Pharmacy, University of Waterloo, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada.
authors.forename: Nawaz
authors.initials: N
authors.lastname: Ahmed
authors.affiliation: Department of Biology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Heikkila
authors.affiliation: School of Pharmacy, University of Waterloo, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada. Electronic address: mbeazely@uwaterloo.ca.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beazely
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000819:agonists / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D020797:Receptor, Platelet-Derived Growth Factor beta; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin; D058826:Serotonin 5-HT2 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Fluoxetine; Heterologous desensitization; Platelet-derived growth factor receptor; Serotonin; Transactivation