Serotonin transactivation of PDGFβ receptors results in a heterologous desensitization to subsequent transactivation stimuli

Abstract

The platelet‐derived growth factor receptor type β (PDGFRβ) is an important receptor tyrosine kinase for neuronal development and survival. In addition to being activated by PDGF ligands, PDGFRβ can be transactivated by G protein‐coupled receptors (GPCRs), an intracellular, ligand‐independent mechanism for activating growth factor receptors. Treatment of primary cortical neurons and SH‐SY5Y cells with 5‐HT results in a transactivation of PDGFRβ and an activation of ERK1/2. Pretreatment of these cells with fluoxetine, a serotonin‐selective reuptake inhibitor (SSRI) appears to block 5‐HT‐induced transactivation of PDGFRβ. However, we demonstrate that fluoxetine itself is able to transactivate PDGFRβ, possibly by binding 5‐HT2 receptors, and this initial transactivation prevents or desensitizes PDGFRβ to subsequent transactivation stimuli. To our knowledge this is the first report of a heterologous desensitization of the transactivation phenomenon. Given the recent development of the “neurotrophic factor hypothesis” for depression, the ability of fluoxetine to transactivate PDGFRβ provides an intriguing link between this widely‐used anti‐depressant drug and promoting growth factor receptor activity in neurons. This work was support by the National Science and Engineering Research Council of Canada.