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Fluoxetine-induced transactivation of the platelet-derived growth factor type β receptor reveals a novel heterologous

Jeff S Kruk1, Maryam S Vasefi1, Nyasha Gondora1

  • 1School of Pharmacy, University of Waterloo, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada.

Molecular and Cellular Neurosciences
|February 24, 2015
PubMed

Insights

Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine can block serotonin-induced receptor tyrosine kinase (RTK) transactivation. This study reveals a transient "blackout" period in RTK signaling following initial SSRI exposure.

Area of Science:

  • Cellular signaling pathways
  • Neuropharmacology
  • Receptor tyrosine kinases

Background:

  • G protein-coupled receptors (GPCRs) and serotonin (5-HT) receptors can activate receptor tyrosine kinases (RTKs) through transactivation.
  • Serotonin-selective reuptake inhibitors (SSRIs) have been shown to block 5-HT-induced transactivation of the platelet-derived growth factor (PDGF) type β receptor.

Purpose of the Study:

  • To investigate the effect of SSRI pretreatment on 5-HT-induced PDGFβ receptor transactivation.
  • To elucidate the mechanism behind the observed blockage of transactivation.

Main Methods:

  • SH-SY5Y cells were pretreated with fluoxetine, followed by stimulation with 5-HT.
  • PDGFβ receptor phosphorylation was measured to assess transactivation.
  • The effect of 5-HT pretreatment on dopamine-induced PDGFβ receptor transactivation was examined.

Main Results:

  • Fluoxetine pretreatment (45 min) initially transactivated the PDGFβ receptor via 5-HT2 receptor activation.
  • Following fluoxetine exposure, subsequent 5-HT stimulation failed to re-transactivate the PDGFβ receptor.
  • 45-min, but not 3-h, 5-HT pretreatment blocked dopamine-induced PDGFβ receptor transactivation, indicating heterologous desensitization.

Conclusions:

  • This study demonstrates a novel short-term "blackout" period in RTK transactivation signaling.
  • Heterologous desensitization of RTK transactivation pathways is possible and occurs rapidly.
  • Findings reveal a previously unknown regulatory mechanism in GPCR-RTK cross-talk.
Keywords:
FluoxetineHeterologous desensitizationPlatelet-derived growth factor receptorSerotoninTransactivation

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