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 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.
['Asano|Masaya|M|', 'Motoike|Serika|S|', 'Yokota|Chika|C|', 'Usuki|Naoto|N|', 'Yamamoto|Hikaru|H|', 'Urabe|Tomoaki|T|', 'Katarao|Kazusa|K|', 'Hide|Izumi|I|', 'Tanaka|Shigeru|S|', 'Kawamoto|Masashi|M|', 'Irifune|Masahiro|M|', 'Sakai|Norio|N|']
D000818:Animals D019556:COS Cells D002462:Cell Membrane D002522:Chlorocebus aethiops D059865:Endoplasmic Reticulum Stress D055785:Gene Knockdown Techniques D009154:Mutation D010620:Phenazocine D021381:Protein Transport D017480:Receptors, sigma D050486:Serotonin Plasma Membrane Transport Proteins
SKF-10047 Sigma-1 receptor Membrane trafficking Serotonin transporter