In Vivo and In Vitro Analyses of Novel Peptidomimetic Disruptors for the Serotonin 5-HT2C Receptor Interaction With Phosphatase and Tensin Homolog

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

doi:10.3389/fphar.2019.00907

In Vivo and In Vitro Analyses of Novel Peptidomimetic Disruptors for the Serotonin 5-HT_2C Receptor Interaction With Phosphatase and Tensin Homolog

Front Pharmacol. 2019 Aug 23:10:907. doi: 10.3389/fphar.2019.00907. eCollection 2019.

Authors

Claudia A Soto¹, Huang-Chi Du², Robert G Fox¹, Taegyun Yang², James Hooson², Noelle C Anastasio¹, Scott R Gilbertson², Kathryn A Cunningham¹

Affiliations

¹ Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
² Department of Chemistry, University of Houston, Houston, TX, United States.

Abstract

Hypofunction of the serotonin (5-HT) 5-HT_2C receptor (5-HT_2CR) has been implicated in a variety of disorders including substance use disorders. As such, approaches to enhance 5-HT_2CR signaling display therapeutic potential. In the present study, we show that disruption of the 5-HT_2CR interaction with the protein phosphatase and tensin homolog (PTEN) via peptidomimetics enhances 5-HT_2CR-mediating signaling in vitro and potentiates selective 5-HT_2CR agonists in behavioral rodent models. Overall, the present study provides further evidence that 5-HT_2CR 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.

Keywords: drug discrimination; peptidomimetics; protein phosphatase and tensin homolog; protein–protein interactions; serotonin 5-HT2C receptor.