and Analyses of Novel Peptidomimetic Disruptors for the Serotonin 5-HT Receptor Interaction With Phosphatase and Tensin Homolog.

Hypofunction of the serotonin (5-HT) 5-HT receptor (5-HTR) has been implicated in a variety of disorders including substance use disorders. As such, approaches to enhance 5-HTR signaling display therapeutic potential. In the present study, we show that disruption of the 5-HTR interaction with the protein phosphatase and tensin homolog (PTEN) peptidomimetics enhances 5-HTR-mediating signaling and potentiates selective 5-HTR agonists in behavioral rodent models. Overall, the present study provides further evidence that 5-HTR 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 G protein-coupled receptors (GPCRs) for new therapeutic development through mechanisms that may display clinical utility.