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Role of Inositol Polyphosphates in Ca^<2+> Homeostasis

肌醇多磷酸盐在 Ca^<2 > 稳态中的作用

基本信息

批准号：
01570139
负责人：
HIRATA Masato
金额：
$ 1.34万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570139/
关键词：
IP_3 analogs IP_3 phosphatase IP_3 kinase IP_3 receptor Ca^<2+> ion IP_3 affinity column 光親和性標識

项目摘要

A series of inositol 1.4.5-trisphosphate (IP_3) analogs, with a bulky substituent on the 2nd carbon of the inositol ring, has been synthesized and examined to explore the structure-activity relationships among IP_3-5-phosphatase. IP_3-3-kinase, and IP_3 binding protein. All analogs (racemic mixtures) inhibited the hydrolysis of [^3H] IP_3 catalyzed by erythrocyte ghosts. With a lower Ki value than seen with IP_3. The effective enantiomer in this process was found to be L-type. The analogs were capable of inhibiting the phosphorylation of [^3H] IP_3 to [^3H] IP_4 by brain cytosol. Although higher concentrations than IP_3 were required. By lowering free Ca^<2+>, the concentrations required for the inhibition became low. In this reaction. the D-enantiomer was effective. The D-enantiomer of these compoundsalso inhibited the binding of [^3H] IP_3 to cerebellum microsomes, With the same potency as seen with IP_3. And they acted as a full agonists in releasing Ca^<2+> from permeabilized macrophages. These results indicate that the 2nd position of IP_3 can be modified with only minor reduction in potency in several assay systems. Thus, the IP_3 analogs synthesized here may be linked to other molecules without loss of their biological activities. For example, the IP_3 analogs were coupled with Sepharose 4B to make IP_3 affinity columns, and the columns were proved to be useful for purifying the IP_3-recognizing proteins.

合成了一系列肌醇1.4.5-三磷酸(IP_3)类似物，并研究了IP_3-5-磷酸酶的构效关系。IP_3-3-激酶和IP_3结合蛋白。所有类似物(外消旋混合物)均能抑制[~3H]IP_3在红细胞膜上的降解。该过程中的有效对映体为L对映体。这些类似物能抑制脑胞浆将[~(3 H)]IP_3磷酸化为[~(3 H)]IP_4。虽然需要比IP_3更高的浓度。通过降低游离Ca~(2+)的浓度，抑制作用所需的浓度降低。在这个反应中。D-对映体是有效的。这些化合物的D-对映体也抑制[~3H]IP_3与小脑微粒体的结合，其效力与IP_3相同。它们还能作为通透性巨噬细胞释放Ca~(2+)的完全激动剂。这些结果表明，在几种测定体系中，IP_3的第二位可以被修饰，但效力只会有轻微的降低。因此，本文合成的IP_3类似物可以在不损失生物活性的情况下与其他分子相连。例如，将IP_3类似物与Sepharose4B偶联，制成IP_3亲和层析柱，该柱可用于纯化IP_3识别蛋白。