Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells

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 SERT-transfected...

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Main Authors: Masayuki Fujiwara, Hikaru Yamamoto, Tatsuhiro Miyagi, Takahiro Seki, Shigeru Tanaka, Izumi Hide, Norio Sakai
Format: Article
Language:English
Published: Elsevier 2013-01-01
Series:Journal of Pharmacological Sciences
Online Access:http://www.sciencedirect.com/science/article/pii/S134786131930324X
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spelling doaj-f91c093133a245e5b6a4f5984d922fa82020-11-24T21:49:55ZengElsevierJournal of Pharmacological Sciences1347-86132013-01-0112227183Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 CellsMasayuki Fujiwara0Hikaru Yamamoto1Tatsuhiro Miyagi2Takahiro Seki3Shigeru Tanaka4Izumi Hide5Norio Sakai6Department of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Corresponding author. nsakai@hiroshima-u.ac.jpThe 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 SERT-transfected 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. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.12194FP] Keywords:: serotonin transporter, chemical chaperone, membrane trafficking, ER stresshttp://www.sciencedirect.com/science/article/pii/S134786131930324X
collection DOAJ
language English
format Article
sources DOAJ
author Masayuki Fujiwara
Hikaru Yamamoto
Tatsuhiro Miyagi
Takahiro Seki
Shigeru Tanaka
Izumi Hide
Norio Sakai
spellingShingle Masayuki Fujiwara
Hikaru Yamamoto
Tatsuhiro Miyagi
Takahiro Seki
Shigeru Tanaka
Izumi Hide
Norio Sakai
Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells
Journal of Pharmacological Sciences
author_facet Masayuki Fujiwara
Hikaru Yamamoto
Tatsuhiro Miyagi
Takahiro Seki
Shigeru Tanaka
Izumi Hide
Norio Sakai
author_sort Masayuki Fujiwara
title Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells
title_short Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells
title_full Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells
title_fullStr Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells
title_full_unstemmed Effects of the Chemical Chaperone 4-Phenylbutylate on the Function of the Serotonin Transporter (SERT) Expressed in COS-7 Cells
title_sort effects of the chemical chaperone 4-phenylbutylate on the function of the serotonin transporter (sert) expressed in cos-7 cells
publisher Elsevier
series Journal of Pharmacological Sciences
issn 1347-8613
publishDate 2013-01-01
description 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 SERT-transfected 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. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.12194FP] Keywords:: serotonin transporter, chemical chaperone, membrane trafficking, ER stress
url http://www.sciencedirect.com/science/article/pii/S134786131930324X
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