Modulation of serotonin transporter function by kappa-opioid receptor ligands

Abstract

Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders. Detailing the molecular events of KOR-linked SERT regulation is important for examining the postulated role of this protein in mood disorders. In this study, we used heterologous expression systems and native tissue preparations to determine the cellular signaling cascades linked to KOR-mediated SERT regulation. KOR agonists U69,593 and U50,488 produced a time and concentration dependent KOR antagonist-reversible decrease in SERT function. KOR-mediated functional down-regulation of SERT is sensitive to CaMKII and Akt inhibition. The U69,593-evoked decrease in SERT activity is associated with a decreased transport Vmax, reduced SERT cell surface expression, and increased SERT phosphorylation. Furthermore, KOR activation enhanced SERT internalization and decreased SERT delivery to the membrane. These data demonstrate that KOR activation decreases 5-HT uptake by altering SERT trafficking mechanisms and phosphorylation status to reduce the functional availability of surface SERT.

Glycogen synthase kinase‐3ß supports serotonin transporter function and trafficking in a phosphorylation‐dependent manner

“…(4-(4-Fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole) (Cat# 513030-Calbiochem), SERT (SR-12) were generated by our laboratory and their specificity were thoroughly characterized in our previous studies and published (Annamalai et al, 2012;Jayanthi et al, 2005;Rajamanickam et al, 2015;Ramamoorthy et al, 2007;Samuvel et al, 2005;Sundaramurthy et al, 2017). SERT-SR-12 will be shared upon reasonable request.…”

“…CHIR99021 treatment significantly decreased mSERT phosphorylation in a dose-dependent manner (one-way ANOVA: F (5,14) = 26.12, p < .0001). Bonferroni's multiple comparison test: **p = .0015, ****p < .0001 compared with vehicle V: Vehicle, CHIR: CHIR99021 (Annamalai et al, 2012;Jayanthi et al, 2005;Rajamanickam et al, 2015;Ramamoorthy et al, 2007;Samuvel et al, 2005;Sundaramurthy et al, 2017…”

Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine

“…SERT is a transmembrane transport protein which is predominantly expressed by essentially all epithelial cells of the intestinal mucosa 21 , 22 . It re-uptakes excessive 5-HT from effective location to terminate its physiological effects, and involves in regulating gastrointestinal motility 18 , 23 . Interestingly, Yano JM et al .…”

Genetic deletion ofRgs12in mice affects serotonin transporter expression and functionin vivoandex vivo

“…We recently identified the mechanism by which RGS12 modulates DAT expression/function, that is differential effects on the heterotrimeric G protein and β-arrestin signaling pathways originating from kappa opioid receptor (KOR) activation (Gross et al, 2019). As dynorphin in the ventral striatum can elicit local stimulation of serotonin reuptake (Schindler et al, 2012), and KOR ligands can also modulate SERT function (Sundaramurthy et al, 2017), it is possible that the effects of RGS12 on SERT expression/function are similarly mediated by KOR or another GPCR.…”