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
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
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DOI：
10.1016/j.jphs.2018.11.005
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发表时间：
2019-01-01
影响因子：
3.5
通讯作者：
Sakai, Norio
中科院分区：
文献类型：
--
作者：
Asano, Masaya;Motoike, Serika;Sakai, Norio
5-羟色胺转运蛋白（SERT）通过膜运输进行功能调节。我们以前的研究已经证明，SERT C-末端缺失突变体（SERTDCT）显示出其膜运输的强烈减少，并保留在内质网（ER）中，这表明SERT Delta CT是一种未折叠的蛋白质，可能会导致ER应激。据报道，σ-1受体（SigR 1）通过其伴侣活性减弱ER应激。在这项研究中，我们研究了原型SigR 1激动剂SKF-10047对COS-7细胞中表达的SERT和SERT Delta CT的膜运输和摄取活性的影响。24小时的SKF-10047处理（>200 μ M）加速了SERT膜运输，并强烈上调了SERT Delta CT活性。有趣的是，SKF-10047对SERT功能的这些影响也在SigR 1表达被shRNA敲低的细胞中发现，这表明SKF-10047通过独立于SigR 1的机制对SERT产生这些影响。一项cDNA阵列研究确定了几个参与SKF-10047作用机制的候选基因。其中，SNARE复合物的成员Syntaxin 3在SKF-10047处理48小时后显著上调。这些结果表明SKF-10047是ER应力缓解的候选物。(c)2018作者Elsevier B. V.代表日本药理学会制作和主办。这是一个在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTDCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERT Delta CT 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 SERT Delta CT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 mu M) accelerated SERT membrane trafficking and robustly upregulated SERT Delta CT 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. (c) 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).