title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Santhanalakshmi
authors.initials: S
authors.lastname: Sundaramurthy
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Balasubramaniam
authors.initials: B
authors.lastname: Annamalai
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Devadoss J
authors.initials: DJ
authors.lastname: Samuvel
authors.affiliation: Integrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Toni S
authors.initials: TS
authors.lastname: Shippenberg
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Lankupalle D
authors.initials: LD
authors.lastname: Jayanthi
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: sammanda.ramamoorthy@vcuhealth.org.
authors.forename: Sammanda
authors.initials: S
authors.lastname: Ramamoorthy
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin
keywords: Clearance; Kappa opioid receptor; Phosphorylation; Serotonin; Serotonin transporter; Trafficking