Abstract
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 peptidomimetics 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 G protein-coupled receptors (GPCRs) for new therapeutic development through mechanisms that may display clinical utility.
Highlights
The serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is a G protein-coupled receptor (GPCR) that is engaged in normal physiology (Heisler et al, 2003), while 5-HT2CR dysfunction is implicated in multiple pathological disorders (Miller, 2005; Howell and Cunningham, 2015)
We first investigated the effects of the parent peptide TAT-r3L4F (3; Figure 1) with the use of a two-lever, water-reinforced drug discrimination paradigm in two separate cohorts of rats as a measure of intrinsic 5-HT2CR agonist activity in vivo (Figure 2)
These results are consistent with previously published cellular assays in which h3L4F lacks intrinsic efficacy to induce 5-HT2CRassociated intracellular signaling but enhances 5-HT2CR signaling in vitro and potentiates the behavioral effects of a selective 5-HT2CR agonist in vivo (Ji et al, 2006; Anastasio et al, 2013)
Summary
The serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is a G protein-coupled receptor (GPCR) that is engaged in normal physiology (e.g., appetite) (Heisler et al, 2003), while 5-HT2CR dysfunction is implicated in multiple pathological disorders (e.g., anxiety, depression, obesity, substance use disorders) (Miller, 2005; Howell and Cunningham, 2015). Genetic, biochemical, and pharmacological analyses have implicated 5-HT2CR hypofunction as a regulator of behaviors (for review, see Cunningham and Anastasio, 2014; Howell and Cunningham, 2015; Di Giovanni and De Deurwaerdere, 2016). Best characterized is coupling of the 5-HT2CR to Gαq/11 proteins to activate phospholipase Cβ (PLCβ), resulting in increased intracellular calcium (Cai2+) release, among various other signaling outcomes (Millan et al, 2008). One protein–protein interaction of interest is the interaction between the 5-HT2CR and accessory protein phosphatase and tensin homolog (PTEN) that occurs at the third intracellular loop of the
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