In vivo and in vitro analyses of novel peptidomimetic disruptors for the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog (PTEN)

Claudia Soto, Huang Chi Du, Robert Fox, Taegyun Yang, James Hooson, Noelle C. Anastasio, Scott R. Gilbertson, Kathryn A. Cunningham, Kathryn A. Cunningham, Scott R. Gilbertson

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Hypofunction of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in a variety of disorders including substance use disorders. As such, approaches to enhance 5-HT2CR signaling display therapeutic potential. In the present study, we show that disruption of the 5-HT2CR interaction with the protein phosphatase and tensin homolog (PTEN) via peptidomimetic-based protein-protein interaction disrupters enhances 5-HT2CR-mediating signaling in vitro and potentiates selective 5-HT2CR agonists in behavioral rodent models. Overall, the present study provides further evidence that 5-HT2CR activity can be modulated through an allosteric protein-protein interaction. This work provides the groundwork for the continued exploration of protein-protein interactions that can allosterically modulate this critical receptor and other important GPCRs for new therapeutic development through mechanisms that may display clinical utility.

Original languageEnglish (US)
Article number907
JournalFrontiers in Pharmacology
Issue numberJULY
StatePublished - Jan 1 2019



  • Drug discrimination
  • Peptidomimetics
  • Protein phosphatase and tensin homolog
  • Protein-protein interactions
  • Serotonin 2C receptor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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