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Study of the IP_3 receptor family and its diverse roles in various physiological functions

IP_3受体家族及其在多种生理功能中的多种作用的研究

基本信息

批准号：
05455006
负责人：
FURUICHI Teiichi
金额：
$ 4.74万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

In this study, we have analyzed the structural and functional diversity of the IP_3 receptor family.1.We have cloned human type 1,2, and 3 receptor cDNAs of the IP_3R family, and have studied their structures, IP_3-binding activities, expression in various tissues and cell-lines, and chromosomal loci.2.We have localized the IP_3-binding site, calmodulin binding site and two N-linked glycosylation sites on the mouse type 1 IP_3 receptor. We have proposed a membrane-spanning model and a channel pore region.3.We have studied the expression of the type 1 receptor in various cell systems ; the up-regulation during the differentiation of a HL-60 cell line toward a neutrophilic cell lineage, the down-regulation in an SH-SY5Y neuroblastoma chronically stimulated with carbacol, and the reduction in cerebella of human spinocerebellar degeneration patients (olivopontocerebellar atrophy [OPCA] and hereditary cerebellar atrophy of Holmes type).4.We have developed transgenic mice carrying the fusion gene composed of the type 1 receptor promoter and beta-galactosidase gene, by which dynamic expression of the type 1 receptor can be easily visualized by assaying beta-galactosidase activity with chromogenic substrates.5.We have studied the expression of other molecules involved in calcium increase in neuronal cells, i.e., ryanodine receptors and voltage-dependent calcium channels, and have suggested the presence of complex calcium signalling systems in the nervous system.

在本研究中，我们分析了IP_3受体家族的结构和功能多样性。我们克隆了人类IP_3R家族的1型、2型和3型受体cdna，并研究了它们的结构、ip_3结合活性、在各种组织和细胞系中的表达以及染色体位点。我们在小鼠1型IP_3受体上定位了IP_3结合位点、钙调素结合位点和两个n -链糖基化位点。我们提出了一个跨膜模型和一个通道孔区。我们研究了1型受体在不同细胞系统中的表达；在HL-60细胞系向中性粒细胞细胞系分化过程中的上调，在长期受乙醇刺激的SH-SY5Y神经母细胞瘤中的下调，以及人脊髓性小脑变性（olivopontocerebellar atrophy [OPCA]和遗传性Holmes型小脑萎缩）患者小脑的减少。我们培育了携带由1型受体启动子和-半乳糖苷酶基因组成的融合基因的转基因小鼠，通过用显色底物检测-半乳糖苷酶活性，可以很容易地观察到1型受体的动态表达。我们研究了神经元细胞中参与钙增加的其他分子的表达，即ryanodine受体和电压依赖性钙通道，并提出在神经系统中存在复杂的钙信号系统。