Research for modulation of expression of serotonin transporter and its involvement in mental disorder

血清素转运蛋白表达调节及其与精神障碍的关系研究

基本信息

批准号：
09670091
负责人：
SAITO Naoaki
金额：
$ 2.05万
依托单位：
KOBE UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670091/
关键词：
serotonin transporter interferon phosphorylation depression synapse electron microscopy 脱リン酸化変異体 COS-7細胞

项目摘要

We examined the regulatory mechanism of serotonin transporter and the involvement of serotonin transporter (SET) in depression to elucidate the function role of SET in mental disorder.1. Regulation of SET by phosphorylation. The regulation of SET expressed in COS7 cells by the activation of protein kinase C with phorbol ester or by inhibition of protein phosphatases with calyculin A was examined. Both treatment decreased the activity of SET with a reduction in Vmax without affecting Km. Site-directed mutagenesis of five putative PKC phosphorylation sites in SET revealed that these inhibitory modulation of SET activity did not act via direct phosphorylation of SET by PKC.2. Immunocytochemical localization of SET.The cellular and intracellular localization of SET was examined by immunocytochemistry. SET was localized in the varicose nerve fibers and nerve terminals but not in the cell bodies. Under electron microscopy, SET was seen around the synaptic vesicles as well as presynaptic membrane.3. The effects of interferon-alpha and -gamma on the transcription of SET.Both SET mRNA and SET activity were increased by treatment with interferon-alpha and -gamma for 3 h. Treatment with dibutyryl cAMP also increased SET mRNA and SET activity. The level of SET mRNA was increased both in the midbrain and adrenal glands of mice which were treated with interferons for 3 h. These results suggest that the interferon-induced psychiatric side effects arise through regulation of serotonin transporter transcription and that the transcriptional regulation of the serotonin transporter is a possible neurochemical mechanism of affective disorders.

我们检查了5-羟色胺转运蛋白的调节机制以及抑郁症中5-羟色胺转运蛋白（SET）的参与，以阐明集合在精神障碍中的功能作用。1。调节磷酸化设置。通过检查蛋白激酶C的蛋白激酶C的激活或通过抑制Calyculin A的蛋白质磷酸酶来调节蛋白激酶C的调节。两种处理都降低了集合的活性，而Vmax的降低而不会影响KM。 SET中五个假定PKC磷酸化位点的位置定向诱变表明，这些抑制性调节的集合活性不是通过PKC.2的SET直接磷酸化来起作用。 SET的免疫细胞化学定位。通过免疫细胞化学检查了SET的细胞和细胞内定位。集合位于静脉曲张纤维和神经末端，但不在细胞体中。在电子显微镜下，在突触囊泡以及突触前膜周围看到了套件。3。干扰素 -α和-gamma对set的转录的影响。通过用干扰素 -α和-gamma处理3小时，set mRNA和set活性都会增加。用二丁酰基cAMP处理也增加了设定的mRNA和设定活性。在用干扰素处理3小时的小鼠中脑和肾上腺中，固定mRNA的水平都升高。这些结果表明，干扰素诱导的精神副作用是通过调节5-羟色胺转录的调节而产生的，而5-羟色胺转运蛋白的转录调节是情感障碍的神经化学机制。