Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor.
Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor.
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DOI：
10.1002/syn.21549
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发表时间：
2012-07
期刊：
影响因子：
2.3
通讯作者：
Su, Tsung-Ping
中科院分区：
文献类型：
--
作者：
Fujimoto, Michiko;Hayashi, Teruo;Urfer, Roman;Mita, Shiro;Su, Tsung-Ping
关键词：
sigma-1受体（Sig-1 R）是一种新型的内质网分子伴侣，调节蛋白质的折叠和降解。已知激动剂激活的Sig-1 R可改善记忆，促进细胞存活，并在动物中发挥抗抑郁剂样作用。选择性Sig-1 R配体Cutamesine（SA 4503）可增加大鼠海马BDNF的表达。细胞内伴侣Sig-1 R或相关配体如何确切地引起BDNF或任何其他神经营养因子的增加尚不清楚。我们在这里检查是否Sig-1 Rs的行动可能与BDNF在神经母细胞瘤细胞系中的翻译后加工和释放有关。我们使用体外试验，并证实cutamesine具有真正的Sig-1 R激动剂的属性，通过引起BiP从Sig-1 Rs的解离。Sig-1 Rs的C-末端通过在体外完全阻断BDNF和GDNF的聚集而发挥强大的伴侣活性。在大鼠B104神经母细胞瘤中，用皮美辛慢性治疗引起BDNF分泌的时间和剂量依赖性增强，而不影响BDNF的mRNA水平。Cutamesine降低细胞内pro-BDNF和成熟BDNF的水平，而增加细胞外成熟BDNF的水平。脉冲追踪实验表明，敲低Sig-1 Rs基因后，B104细胞分泌的成熟BDNF减少，但不影响BDNF的合成。我们的研究结果表明，与临床上使用的抗抑郁药，促进BDNF的转录上调，Sig-1 R激动剂cutamesine增强神经营养因子的翻译后加工。这种独特的药理学特征可能为神经精神疾病的治疗提供新的治疗机会。
The sigma-1 receptor (Sig-1R) is a novel endoplasmic reticulum (ER) molecular chaperone that regulates protein folding and degradation. The Sig-1R activation by agonists is known to improve memory, promote cell survival, and exert an antidepressant-like action in animals. Cutamesine (SA4503), a selective Sig-1R ligand, was shown to increase BDNF in the hippocampus of rats. How exactly the intracellular chaperone Sig-1R or associated ligand causes the increase of BDNF or any other neurotrophins is unknown. We examined here whether the action of Sig-1Rs may relate to the post-translational processing and release of BDNF in neuroblastoma cell lines. We used in vitro assays and confirmed that cutamesine possesses the bona fide Sig-1R agonist property by causing the dissociation of BiP from Sig-1Rs. The C-terminus of Sig-1Rs exerted robust chaperone activity by completely blocking the aggregation of BDNF and GDNF in vitro. Chronic treatment with cutamesine in rat B104 neuroblastoma caused a time- and dose-dependent potentiation of the secretion of BDNF without affecting the mRNA level of BDNF. Cutamesine decreased the intracellular level of pro-BDNF and mature BDNF whereas increased the extracellular level of mature BDNF. The pulse-chase experiment indicated that the knockdown of Sig-1Rs decreased the secreted mature BDNF in B104 cells without affecting the synthesis of BDNF. Our findings indicate that, in contrast to clinically used antidepressants that promote the transcriptional upregulation of BDNF, the Sig-1R agonist cutamesine potentiates the post-translational processing of neurotrophins. This unique pharmacological profile may provide a novel therapeutic opportunity for the treatment of neuropsychiatric disorders.
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影响因子：
4.4
作者：
Matsumoto RR
通讯作者：
Matsumoto RR
影响因子：
2.4
作者：
Donnici L;Tiraboschi E;Tardito D;Musazzi L;Racagni G;Popoli M
通讯作者：
Popoli M
影响因子：
14.5
作者：
Ruscher, Karsten;Shamloo, Mehrdad;Wieloch, Tadeusz
通讯作者：
Wieloch, Tadeusz
靶向配体的伴侣伴侣Sigma-1受体在神经精神疾病的治疗中。
影响因子：
5.8
作者：
Hayashi T;Tsai SY;Mori T;Fujimoto M;Su TP
通讯作者：
Su TP
DOI：
10.3390/ph4060880
发表时间：
2011
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Katz JL;Su TP;Hiranita T;Hayashi T;Tanda G;Kopajtic T;Tsai SY
通讯作者：
Tsai SY