title: Effects of the chemical chaperone 4-phenylbutylate on the function of the serotonin transporter (SERT) expressed in COS-7 cells.
abstract: The serotonin transporter (SERT) is involved in various psychiatric disorders, including depression and autism. Recently, chemical chaperones have been focused as potential therapeutic drugs that can improve endoplasmic reticulum (ER) stress-related pathology. In this study, we used SERTtransfected COS-7 cells to investigate whether 4-phenylbutylate (4-PBA), a chemical chaperone, affects the membrane trafficking and uptake activity of SERT. Treatment with 4-PBA for 24 h dose-dependently increased the uptake activity of SERT. In accordance with increased SERT activity, the expression of maturely glycosylated SERT was increased, while the expression of immaturely glycosylated SERT was decreased. This finding suggests that 4-PBA increased the functional SERT with mature glycosylation via accelerating its folding and trafficking. 4-PBA also increased the activity of the C-terminus-deleted mutant SERT (SERTΔCT), which was stacked in the ER, and decreased SERTΔCT-induced ER stress, further supporting the idea that 4-PBA acts as a chemical chaperone for SERT. Imaging studies showed that fluorescence-labeled SERT was gradually and significantly translocated to the plasma membrane by 4-PBA. These results suggest that 4-PBA and related drugs can potentially affect serotonergic neural transmission by functioning as chaperones, thereby providing a novel therapeutic approach for SERT-related diseases.
authors.affiliation: Department of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Miyagi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tanaka
authors.forename: Izumi
authors.initials: I
authors.lastname: Hide
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D001523:Mental Disorders / Q000209:etiology / Q000628:therapy; D058990:Molecular Targeted Therapy; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D059326:Serotonergic Neurons / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism* / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D010654:Phenylbutyrates; D050486:Serotonin Plasma Membrane Transport Proteins; C075773:4-phenylbutyric acid