Novel interactions of Slo1 channel and Thromboxane A2 receptor in blood vessels

血管中 Slo1 通道和血栓素 A2 受体的新相互作用

基本信息

  • 批准号:
    7695542
  • 负责人:
  • 金额:
    $ 65.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-01 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

Our long term goal is to obtain an integral view of the mechanisms by which Thromboxane A2- prostanoid receptor (TPR) and the large conductance Ca2+-activated K+ channel (MaxiK, BK) interact with each other to regulate vascular function. TPR and MaxiK play significant roles in determining vascular health. In addition, both proteins are known to be involved in the modulation of tumorigenesis and myocardial infarction. In coronary arteries, TPR are activated by the prostanoid thromboxane A2 (TXA2) leading to powerful vasoconstrictions; while MaxiK channel aided by its β1 subunit can fine tune arterial tone determined by the degree of channel activity. Our early work showed that TXA2 mimetic U46119 inhibits MaxiK channel activity in membranes from coronary smooth muscle reconstituted in lipid bilayers, which suggested a strong functional association between both TPR and MaxiK that endured dissociative reconstitution procedures. Recent preliminary experiments also show that: 1) TPR modulates MaxiK pore-forming α subunit (Slo1) via a novel mechanism that is G-protein independent, where MaxiK channel activity can be reduced by the specific TPR agonist U46619, 2) TPR and MaxiK channel subunits form heteromultimeric complexes in native arteries and in expression systems, 3) TPR and MaxiK channel functional coupling occurs in native human coronary arterial myocytes and can be reproduced after ectopic expression of TPR and Slo1, and 4) agonist-stimulation enhances TPR and Slo1 association. Here, we will test the hypothesis that agonist stimulation changes TPR-Slo1-β1 associations resulting in Slo1 channel inhibition. The specific aims are to: 1. Unravel the molecular mechanism(s) of Slo1 channel inhibition by agonist (U46619)- activated TPR, and 2. Define the role of β1 subunit in agonist-TPR-Slo1 channel inhibition. Experiments will be performed using modern approaches such as biochemistry, molecular biology, and opto-biophysical methods including fluorescence microscopy at the diffraction limit. Because of the broad impact of MaxiK and TPR in mammalian physiology, the knowledge derived from these studies may provide new opportunities for the prevention of disease not only in the cardiovascular system but in other systems as well.
我们的长期目标是获得血栓素A2-作用机制的整体视图

项目成果

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ENRICO STEFANI其他文献

ENRICO STEFANI的其他文献

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{{ truncateString('ENRICO STEFANI', 18)}}的其他基金

BK(Ca) channel in heart mitochondria
心脏线粒体中的 BK(Ca) 通道
  • 批准号:
    8459912
  • 财政年份:
    2012
  • 资助金额:
    $ 65.39万
  • 项目类别:
BK(Ca) channel in heart mitochondria
心脏线粒体中的 BK(Ca) 通道
  • 批准号:
    8298046
  • 财政年份:
    2012
  • 资助金额:
    $ 65.39万
  • 项目类别:
BK(Ca) channel in heart mitochondria
心脏线粒体中的 BK(Ca) 通道
  • 批准号:
    8628868
  • 财政年份:
    2012
  • 资助金额:
    $ 65.39万
  • 项目类别:
Novel interactions of Slo1 channel and Thromboxane A2 receptor in blood vessels
血管中 Slo1 通道和血栓素 A2 受体的新相互作用
  • 批准号:
    7851419
  • 财政年份:
    2009
  • 资助金额:
    $ 65.39万
  • 项目类别:
Revealing Cardiovascular Stress Regulation beyond the Diffraction Limit
揭示超越衍射极限的心血管压力调节
  • 批准号:
    7410118
  • 财政年份:
    2007
  • 资助金额:
    $ 65.39万
  • 项目类别:
Revealing Cardiovascular Stress Regulation beyond the Diffraction Limit
揭示超越衍射极限的心血管压力调节
  • 批准号:
    7788195
  • 财政年份:
    2007
  • 资助金额:
    $ 65.39万
  • 项目类别:
Revealing Cardiovascular Stress Regulation beyond the Diffraction Limit
揭示超越衍射极限的心血管压力调节
  • 批准号:
    8065410
  • 财政年份:
    2007
  • 资助金额:
    $ 65.39万
  • 项目类别:
Revealing Cardiovascular Stress Regulation beyond the Diffraction Limit
揭示超越衍射极限的心血管压力调节
  • 批准号:
    7251721
  • 财政年份:
    2007
  • 资助金额:
    $ 65.39万
  • 项目类别:
Revealing Cardiovascular Stress Regulation beyond the Diffraction Limit
揭示超越衍射极限的心血管压力调节
  • 批准号:
    7586132
  • 财政年份:
    2007
  • 资助金额:
    $ 65.39万
  • 项目类别:
K Channel & c-Src Signaling Complexes in Smooth Muscle
K频道
  • 批准号:
    6941943
  • 财政年份:
    2004
  • 资助金额:
    $ 65.39万
  • 项目类别:

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