Program

PO1-1-127

SKF-10047, a prototype Sigma-1 receptor agonist, accelerated the membrane trafficking and uptake activity of serotonin transporter and its mutant via the mechanism independent of Sigma-1receptor

[Speaker] Norio Sakai:1
[Co-author] Masaya Asano:1, Chika Yokota:1, Naoto Usuki:1, Hikaru Yamamoto:1, Isumi Hide:1, Shigeru Tanaka:1
1:Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan

The function of serotonin transporter (SERT) is regulated via its membrane trafficking. Our previous studies have revealed that the SERT C-terminal deletion mutant (SERTCT) showed the robust decrease in its membrane trafficking and was retained at endoplasmic reticulum (ER), suggesting that SERTCT would be an unfolded protein. The accumulation of unfolded membrane protein in ER could be the cause of ER stress. It has been reported that the Sigma-1receptor (SigR1) attenuates the ER stress via its chaperone activity. In order to find the drugs that accelerate the membrane trafficking and relieve the ER stress, we investigates the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTCT expressed in COS-7 cells. The 24hr-treatment of SKF-10047 (> 200 M) accelerated the SERT membrane trafficking, and robustly upregulated the activity of SERTCT. Interestingly, these effects of SKF-10047 on SERT functions also remained in the cells in which the SigR1 expression was knocked-down by shRNA, suggesting that SKF-10047 exerted these effects on SERT via a mechanism independent of SigR1. The cDNA array study showed several candidate genes, which is involved in the mechanism of SKF-10047 actions. Among them, syntaxin 3, a cellular receptor for transport vesicles which participate in exocytosis, was significantly upregulated by the treatment of SKF-10047 (> 200 M) for 48 hours. These results suggest that SKF-10047 would be a candidate drug for the relief of ER stress, which caused by the accumulation of unfolded membrane proteins.
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