Modulation of serotonin transporter function by kappa-opioid receptor ligands. (February 2017)

• Record Type: Journal Article
• Authors: Sundaramurthy, Santhanalakshmi; Annamalai, Balasubramaniam; Samuvel, Devadoss J.; Shippenberg, Toni S.; Jayanthi, Lankupalle D.; Ramamoorthy, Sammanda
• Is Part Of: Neuropharmacology. Volume 113:Part A(2017)
• Page Start: 281
• Page End: 292
• Publication Date: 2017-02
• Subjects: Kappa opioid receptor -- Serotonin -- Clearance -- Serotonin transporter -- Phosphorylation -- Trafficking; 5-HT 5-hydroxytryptamine (serotonin) -- Akt X Akt inhibitor X (10-(4′-(N-diethylamino)butyl)-2-chlorophenoxazine) -- Akt protein kinase B/Akt -- BNI nor-binaltorphimine -- CaMKII Calcium calmodulin dependent kinase II -- DAT dopamine transporter -- DMEM Dulbecco's modified Eagle's medium -- GPCR G-protein coupled receptor -- HEK-293 human embryonic kidney cells -- hSERT human SERT -- KOR kappa-opioid receptor -- KRH Krebs-Ringer-HEPES buffer -- NAc nucleus accumbens -- NET norepinephrine transporter -- PAGE polyacrylamide gel electrophoresis -- PBS phosphate buffered saline -- PKC protein kinase C -- PKG protein kinase G -- RIPA radioimmunoprecipitation assay lysis buffer -- SERT serotonin transporter -- SSRI serotonin selective reuptake inhibitors -- TfR transferrin receptor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.10.011
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Highlights: K-opioid receptor agonists produce conditional aversive and pro-depressant-like effects. SERT is one of the major determinants of synaptic 5-HT and serotonergic neurotransmission. K-opioid receptor activation decreases 5-HT uptake through Akt and CaMKII pathways. K-opioid receptor activation decreases surface SERT, increases phosphorylation and endocytosis. K-opioid receptor activation decreases serotonin clearance in the striatum.