SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism
The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTΔCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERT...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861318302068 |
| _version_ | 1818336688477306880 |
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| author | Masaya Asano Serika Motoike Chika Yokota Naoto Usuki Hikaru Yamamoto Tomoaki Urabe Kazusa Katarao Izumi Hide Shigeru Tanaka Masashi Kawamoto Masahiro Irifune Norio Sakai |
| author_facet | Masaya Asano Serika Motoike Chika Yokota Naoto Usuki Hikaru Yamamoto Tomoaki Urabe Kazusa Katarao Izumi Hide Shigeru Tanaka Masashi Kawamoto Masahiro Irifune Norio Sakai |
| author_sort | Masaya Asano |
| collection | DOAJ |
| description | The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTΔCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERTΔCT is an unfolded protein that may cause ER stress. The Sigma-1 receptor (SigR1) has been reported to attenuate ER stress via its chaperone activity. In this study, we investigated the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTΔCT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 μM) accelerated SERT membrane trafficking and robustly upregulated SERTΔCT activity. Interestingly, these effects of SKF-10047 on SERT functions were also found in cells in which SigR1 expression was knocked down by shRNA, suggesting that SKF-10047 exerted these effects on SERT via a mechanism independent of SigR1. A cDNA array study identified several candidate genes involved in the mechanism of action of SKF-10047. Among them, Syntaxin3, a member of the SNARE complex, was significantly upregulated by 48 h of SKF-10047 treatment. These results suggest that SKF-10047 is a candidate for ER stress relief. Keywords: Serotonin transporter, Sigma-1 receptor, Membrane trafficking, SKF-10047 |
| first_indexed | 2024-12-13T14:43:18Z |
| format | Article |
| id | doaj.art-d73623f3346246769ae8dadbf2c820a5 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-13T14:43:18Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-d73623f3346246769ae8dadbf2c820a52022-12-21T23:41:33ZengElsevierJournal of Pharmacological Sciences1347-86132019-01-0113912936SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanismMasaya Asano0Serika Motoike1Chika Yokota2Naoto Usuki3Hikaru Yamamoto4Tomoaki Urabe5Kazusa Katarao6Izumi Hide7Shigeru Tanaka8Masashi Kawamoto9Masahiro Irifune10Norio Sakai11Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, Japan; Department of Dental Anesthesiology, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, Japan; Department of Anesthesiology and Critical Care, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Anesthesiology and Critical Care, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Dental Anesthesiology, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kausmi, Minami-ku, Hiroshima 734-8551, Japan; Corresponding author.The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTΔCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERTΔCT is an unfolded protein that may cause ER stress. The Sigma-1 receptor (SigR1) has been reported to attenuate ER stress via its chaperone activity. In this study, we investigated the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTΔCT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 μM) accelerated SERT membrane trafficking and robustly upregulated SERTΔCT activity. Interestingly, these effects of SKF-10047 on SERT functions were also found in cells in which SigR1 expression was knocked down by shRNA, suggesting that SKF-10047 exerted these effects on SERT via a mechanism independent of SigR1. A cDNA array study identified several candidate genes involved in the mechanism of action of SKF-10047. Among them, Syntaxin3, a member of the SNARE complex, was significantly upregulated by 48 h of SKF-10047 treatment. These results suggest that SKF-10047 is a candidate for ER stress relief. Keywords: Serotonin transporter, Sigma-1 receptor, Membrane trafficking, SKF-10047http://www.sciencedirect.com/science/article/pii/S1347861318302068 |
| spellingShingle | Masaya Asano Serika Motoike Chika Yokota Naoto Usuki Hikaru Yamamoto Tomoaki Urabe Kazusa Katarao Izumi Hide Shigeru Tanaka Masashi Kawamoto Masahiro Irifune Norio Sakai SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism Journal of Pharmacological Sciences |
| title | SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism |
| title_full | SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism |
| title_fullStr | SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism |
| title_full_unstemmed | SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism |
| title_short | SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism |
| title_sort | skf 10047 a prototype sigma 1 receptor agonist augmented the membrane trafficking and uptake activity of the serotonin transporter and its c terminus deleted mutant via a sigma 1 receptor independent mechanism |
| url | http://www.sciencedirect.com/science/article/pii/S1347861318302068 |
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