Physiological Significance of Na,K-pump Diversity

Na,K泵多样性的生理意义

基本信息

项目摘要

DESCRIPTION (provided by applicant): The Na,K-pump (i.e., Na,K-ATPase) is the major pharmacological receptor for cardiac glycosides such as digitalis and ouabain. It is a plasma membrane-spanning protein complex that mediates the exchange of Na+ and K+ at the expense of metabolic energy. The resulting ionic gradients provide the basis for nutrient uptake, control of intracellular pH and Ca++, membrane excitability, and volume regulation. It follows that the Na,K-pump is central to cellular homeostasis. Its component subunits exist in multiple forms, but the physiological relevance of this subunit diversity remains unknown. The primary contributor to overall catalysis, the alpha subunit, exists in 4 isoforms, while an associated protein, the beta subunit, exists in 3. Recent work suggests that the major functional distinction among the isoforms is their interaction with regulatory proteins such as protein kinase C (PKC), which also exist in multiple forms. The 4 specific aims of this project will evaluate explicitly the role played by this protein diversity in regulation. The first aim will use heterologous expression in mammalian cells to evaluate the isoform-specific differences in pump regulation initiated by stimulation of PKCs. The second specific aim will determine the mechanisms underlying the isoform-specific differences, again using the heterologous expression strategy. The third aim will identify the contribution played by isozymes of PKC in the regulation of pump isoforms, using specific inhibitors and genetic techniques to suppress kinase activity. Finally, the fourth specific aim will establish the regulatory consequences of subunit heterogeneity in cells that naturally express multiple forms by suppressing the endogenous isoforms. Taken together, these studies will provide crucial data on the role played by protein diversity in regulation of the pump. More importantly, completion of these studies will increase our overall understanding of subunit diversity and its physiological importance in active Na+, K+ transport. These studies will take advantage of established cell lines in culture. Because of the fundamental role of the Na,K-pump in cellular homeostasis, it lends itself well to the use of these models. Indeed, this project expands the usefulness of existing non-mammalian model systems, consistent with the goals of the NCRR.
描述(由申请人提供):Na,K泵(即,Na,K-ATP酶)是强心苷如洋地黄和哇巴因的主要药理学受体。它是一种跨质膜蛋白复合物,以代谢能量为代价介导Na+和K+的交换。由此产生的离子梯度提供了营养吸收,控制细胞内pH值和Ca++,膜兴奋性和容量调节的基础。由此可见,Na,K泵是细胞内稳态的核心。其组成亚基以多种形式存在,但这种亚基多样性的生理相关性仍然未知。总催化的主要贡献者,α亚基,存在于4种异构体中,而相关的蛋白质,β亚基,存在于3种异构体中。最近的工作表明,主要的功能差异之间的异构体是他们的相互作用与调节蛋白,如蛋白激酶C(PKC),这也存在于多种形式。该项目的4个具体目标将明确评估这种蛋白质多样性在调控中所发挥的作用。第一个目标将使用哺乳动物细胞中的异源表达来评估由PKC刺激启动的泵调节中的亚型特异性差异。第二个具体目标将再次使用异源表达策略来确定亚型特异性差异的机制。第三个目标是确定PKC同工酶在调节泵同工酶中的作用,使用特异性抑制剂和遗传技术来抑制激酶活性。最后,第四个具体的目标将建立调节的亚基异质性的细胞,自然表达多种形式,通过抑制内源性异构体的后果。总之,这些研究将提供关于蛋白质多样性在调节泵中所起作用的关键数据。更重要的是,这些研究的完成将增加我们对亚基多样性及其在主动Na+,K+转运中的生理重要性的整体理解。这些研究将利用培养中已建立的细胞系。由于Na,K-泵在细胞内稳态中的基本作用,它很好地适用于这些模型的使用。事实上,该项目扩大了现有非哺乳动物模型系统的实用性,符合NCRR的目标。

项目成果

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THOMAS A PRESSLEY其他文献

THOMAS A PRESSLEY的其他文献

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{{ truncateString('THOMAS A PRESSLEY', 18)}}的其他基金

CORE-- MOLECULAR BIOLOGY
核心--分子生物学
  • 批准号:
    6107534
  • 财政年份:
    1997
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA, K-PUMP ALPHA ISOFORMS
NA、K-泵 ALPHA 亚型的生理意义
  • 批准号:
    2040199
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
Physiological Significance of Na,K-pump Diversity
Na,K泵多样性的生理意义
  • 批准号:
    7037990
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6938031
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6394640
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6188400
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA, K-PUMP ALPHA ISOFORMS
NA、K-泵 ALPHA 亚型的生理意义
  • 批准号:
    2286373
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6011530
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6639861
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:
PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6540603
  • 财政年份:
    1994
  • 资助金额:
    $ 34.36万
  • 项目类别:

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    1994
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Physiological Significance of Na,K-pump Diversity
Na,K泵多样性的生理意义
  • 批准号:
    7037990
  • 财政年份:
    1994
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    $ 34.36万
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NA,K-泵α亚型的生理意义
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    6938031
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    1994
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    $ 34.36万
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PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
NA,K-泵α亚型的生理意义
  • 批准号:
    6394640
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    $ 34.36万
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PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
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    2286373
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    $ 34.36万
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PHYSIOLOGICAL SIGNIFICANCE OF NA,K-PUMP ALPHA ISOFORMS
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