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Dynamic change in existing form and physiological significance of calcineurin the brain neuronal cells.

脑神经元细胞钙调神经磷酸酶存在形式的动态变化及其生理意义。

基本信息

批准号：
04454138
负责人：
HATASE Osamu
金额：
$ 3.84万
依托单位：
Kagawa Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

We used rat brains to elucidate the diversity of the existing forms of calcineurin and its physiolgical significance.1) Calcineurin does not always exist in a heterodimeric form of A and B subunits (1 : 1). A part of calcineeurin could be present as free A and/or B subunits in the brain. We elucidated that the molar ratio of A/B showed a significant difference among various parts of rat brain. Membranc-bound calcineurin was proven to increase in a calcium-dependent manner. In the latter case, B subunit showed much larger change as compared to A,indicating that both subunits could not always make a complex.2) Calcineurin is abundantly present in brain, especially in hippocampus and striatum. In the kindling model rats, the overexpression of calcineurin was observed in hippocampus. When immunosuppressants such cyclosporin A and FK506 were administered to the kindled rats, they could stop the progression of epileptic stages. This inhibition was reversible and the progression of epileptogenesis started after the drugs were stopped. These data indicates that the enhancement of dephosphorylation of various substrates of calcineurin could be involved in the pathogenesis of epilepsy.3) We analyzed the change in intracellular calcium concentration ([Ca]i) in the cultured neurons of rat hippocampus. When the neutralizing antibody was electrophoretically introdued into these neurons, the increase of [Ca] i was larger than that of control neurons. This increase may be attributed to the stimulation of calcium channeling activity of phosphorylated form of calcium channel which is one of the intrinsic substrates of calcineurin.

我们利用大鼠脑阐明钙调磷酸酶存在形式的多样性及其生理意义。1)钙调磷酸酶并不总是以a和B亚基的异二聚体形式存在（1:1）。钙调磷酸酶的一部分可以作为游离的A和/或B亚基存在于大脑中。我们发现A/B的摩尔比在大鼠脑各部位有显著差异。膜结合钙调磷酸酶被证明以钙依赖的方式增加。在后一种情况下，与A相比，B亚基的变化要大得多，这表明两个亚基并不总是能形成复合物。2)钙调磷酸酶在大脑中大量存在，尤其是海马和纹状体。点燃模型大鼠海马组织中钙调磷酸酶过表达。免疫抑制剂如环孢素A和FK506给予点燃大鼠，它们可以阻止癫痫阶段的进展。这种抑制是可逆的，停药后癫痫发生开始进展。这些数据表明，钙调磷酸酶各种底物的去磷酸化增强可能参与癫痫的发病机制。3)分析大鼠海马培养神经元细胞内钙浓度（[Ca]i）的变化。当电泳将中和抗体引入这些神经元时，[Ca] i的增加幅度大于对照神经元。这种增加可能是由于钙调磷酸酶内在底物之一的磷酸化形式的钙通道活性受到刺激。