别构调节Sigma-1受体抗抑郁作用及其机制研究

Allosteric regulating receptor is an important modulatory mechanism for receptor function.Compared to receptor orthodox ligand, allosteric receptor modulation has tramadous advantage in term of the safety and less adverse effects as drug. Sigma-1 receptor, distributed in CNS, functions as a receptor and chaperon protein, which renders the receptor a complex functions.The antidepression of sigma-1 receptor agonist is actively studied, however, the application of such kind of drug is limited because of the safety concern. We recently discovered a new and potent, with high selectivity, sigma-1 receptor allosteric modulator SOMCL-668, and found SOMCL-668 produced a rapidly antidepressant effects which appears to be associated with production of BDNF in hipocampus. We further found that the effects of BDNF on ERK activation and inhibition of GSK-3β in cutured neurons were dramatically attenuated in the presence of sigma-1 receptor antagonist or in sigma-1 receptor knockdown cells, so was the DNDF-stimulated neurite outgrowth. Indicating that the function of BDNF is dependent on sigma-1 receptor. In the present proposal, we will take the advantage of nearly discovered sigma-1 receptor allosteric modulator SOMCL-668 and investigate the effects of sigma-1 receptor allosteric regulation in the depression and its underlined mechanisms. There are three specific aims: 1. To investigate the effects of chronic SOMCL-668 treatment on dendritic morphology and neurogenesis in either wt or sigma-1 receptor knockout mice; 2. To investigate the signaling mechanism and molecular events between signa-1 receptor and BDNF functional and physical couplings; 3. The electricphysiological studies on sigma-1 - modulated hippocampal functions; This work will provide novel insight on role of sigma-1 receptor in depression and potential new target (allosteric sigma-1 receptor modulation)for antidepressant drug discovery.

受体别构调节是有别于正位配体(ligand)的受体功能调控机制，由于其作用上具有时间和空间选择性因而较之传统的正位配体在安全性和选择上有较大优势。Sigma-1受体既具受体活性又有分子伴侣功能，其生物学功能因此较为复杂。以Sigma-1受体为靶向的抗抑郁研究虽较为活跃,但传统的正位激动剂因为潜在严重副作用而受到限制。我们近来发现别构调节sigma-1受体可产生快速抗抑郁作用，并首次发现sigma-1受体与BDNF存在一个环路调节现象。本项目以此为基础，深入研究sigma-1受体与抑郁症发生发展的分子机制及sigma-1受体别构调节抗抑郁作用，并以具有自我知识产权的国际上首个高选择性、高效sigma-1受体别构调节剂SOMCL-668为手段，对sigma-1受体别构调节抗抑郁作用及机理进行系统研究，为基于sigma-1受体别构调节的抗抑郁药物发现提供新靶点、新策略。

近年研究表明, sigma-1受体在抑郁症发生发展相关,激动sigma-1受体显著改善抑郁。我们以本实验室发现的国际上首个高选择性sigma-1受体别构调节剂SOMCL-668为评价和干预手段，对sigma-1受体别构调节抗抑郁作用及机理进行系统研究。我们发现别构调节剂SOMCL-668显著改善CUMS诱导的小鼠抑郁样症状,其作用与sigma-1刺激的快速BDNF产生有关。我们进一步发现Sigma-1通过了调节Akt/GSK3betta进而调控BDNF表达。进一步我们发现在转染外源性TrK B受体质粒的HEK293T细胞以及原代神经元中，提前给予sigma-1受体拮抗剂均可以阻析BDNF介导 pERK1/2和pS9-GSK3β升高。同时，提前给予sigma-1受体拮抗剂同样可以抑制BDNF引起的原代神经元树突生长。这一现象均在sigma-1受体基因敲除小鼠中得到证实。因此，本课题表明，BDNF-Trk B受体信号通路发挥作用必须依赖于sigma-1受体调控。.电生理研究发现别构调节Sigma-1 受体对海马CA1区域锥体神经元被动膜特性和兴奋性有正向调节作用。虽然Sigma-1受体对成年神经元突触传递有明显影响, 发现Sigma-1 受体敲除并不影响P14小鼠感觉皮层第2/3层椎体神经元的突触传递，且单个神经元兴奋性-抑制性微小突触后电流发放频率的比值（excitatory-inhibitory ratio, E/I rario）也不受Sigma-1受体敲除所影响。