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TWO ISOFORMS OF NA,K-ATPASE IN THE HEART

心脏中 NA,K-ATP 酶的两种异构体

基本信息

批准号：
3471750
负责人：
YUK-CHOW NG
金额：
$ 9.06万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-08-01 至 1994-07-31
项目状态：
已结题

项目摘要

The overall objective of this project is to elucidate the physiological, and pharmacological significance and biochemical regulation of the two molecular forms of Na+,K+ -ATPase in the ferret heart. We have demonstrated that two molecular forms of Na+,K+-ATPase exist in ferret myocardial cells in approximately equal abundance; the high (alpha(alpha(+)) and the low (alpha) molecular with forms correspond to the high and low affinity ouabain binding sites, respectively. Inhibition of the isoenzymes by ouabain caused biphasic positive inotropic effects indicating that both of the alpha subunits are the pharmacological receptors for the cardiac glycosides. Although isoenzymes of Na+,K+-ATPase are widely distributed in different cell types, the physiological significance of having two isoforms of the Na pump in the cardiac cells is unknown. Ferret heart offers a unique opportunity for these studies. In the proposed study, the following experiments will be performed: 1) Possible physiological significance of the two isoforms of the Na pump will be examined. The hypothesis that alpha(+) and alpha forms of the Na pump operate at different rates and that insulin preferentially regulates the alpha(+) form of the Na pump will be tested. Insulin has been shown to stimulate the alpha(+) form of the Na pump of fat cells with no effect on the alpha form of the pump. 2) Relative abundance of the alpha(+) form increases during neonatal and early postnatal development. The hypothesis that these changes are closely related to changes in pharmacological effects of the glycoside and that a low affinity "neonatal" form is common among different species during early development will be tested. 3) The hypothesis that differences in affinity of the alpha subunits for the glycoside results from differences in turnover rate and/or stability of the phosphoenzymes will be examined. 4) The hypothesis that myocardial hypertrophy alters isoenzyme profiles and therefore glycoside sensitivity of the heart will be tested. 5) Thyroid hormone regulates a wide range of physiological functions including the expression of myosin isoenzymes and the total number of Na+,K+-ATPase units. Therefore, the hypothesis that thyroid hormone regulates the expression of the two isoforms of alpha subunits will be tested. Results of these studies will indicate if the relative activity or the relative abundance of two isoforms of Na+,K+-ATPase is under hormonal control or is affected by myocardial hypertrophy, and these changes are associated with alterations in sensitivity to the digitalis glycosides.

该项目的总体目标是阐明生理学、药理学意义和生化意义 Na+,K+ -ATPase 两种分子形式的调节雪貂的心。我们已经证明了两种分子形式 Na+,K+-ATP酶存在于雪貂心肌细胞中约同等丰富；高 (alpha(alpha(+)) 和低 (alpha) 分子的形式对应于高亲和力和低亲和力分别是哇巴因结合位点。同工酶的抑制哇巴因引起的双相正性肌力作用表明两个α亚基都是药理学受体为强心苷。尽管 Na+,K+-ATP 酶的同工酶广泛分布于不同细胞类型中，具有生理心脏中钠泵的两种异构体的重要性细胞未知。雪貂心脏提供了一个独特的机会这些研究。在拟议的研究中，将进行以下实验： 1) 两种异构体可能的生理意义将检查 Na 泵。假设 alpha(+) 和 alpha Na泵的不同形式以不同的速率运行并且胰岛素优先调节 Na 泵的 alpha(+) 形式已测试。胰岛素已被证明可以刺激α（+）形式脂肪细胞的钠泵对脂肪细胞的α形式没有影响泵。 2) α(+)形式的相对丰度在新生儿和产后早期发育。假设这些变化与药理变化密切相关糖苷的作用以及低亲和力的“新生儿”形式在早期发育过程中不同物种之间很常见已测试。 3）亲和力差异的假设糖苷的α亚基是由差异造成的磷酸酶的周转率和/或稳定性将是检查了。 4) 心肌肥厚改变的假说同工酶谱以及心脏的糖苷敏感性将受到测试。 5）甲状腺激素调节多种生理功能，包括肌球蛋白的表达同工酶和 Na+,K+-ATP 酶单位总数。所以，甲状腺激素调节表达的假说将测试两种α亚基亚型。这些研究的结果将表明相对活性或 Na+,K+-ATPase 两种亚型的相对丰度如下荷尔蒙控制或受到心肌肥大的影响，并且这些变化与敏感度的改变有关洋地黄苷。