K-DEPENDENT NA/CA EXCHANGE IN HUMAN PLATELETS

最近的研究表明，人类血小板Na/Ca交换器（NCX）与视网膜棒NCX相同。这种交换剂在血小板钙储存中起着重要的调节作用，它不仅受钠电化学梯度的驱动，而且受血小板质膜上钾电化学梯度的驱动。此外，血小板表达钠泵的α - 3亚型，这是一种对心脏糖苷高度敏感的亚型。血小板离子运输的这些特征将血小板钙代谢与全身钠和钾稳态的波动以及血小板钠泵的活性紧密联系在一起。该项目的核心假设是血小板钙稳态与全身Na/K调节之间的联系，解释了高Na和高K摄入对心血管的一些影响，而这些影响与Na和K摄入对血压的影响无关。三个具体目标将探讨这一假设。Specific Aim 1将破译人类血小板中na泵的生理和分子特征，重点关注这些细胞中的α 3亚基异构体及其对心脏糖苷的敏感性。该结果将更好地了解血小板NCX与钠泵之间的联系。特异性目的2将验证高钠摄入量提高细胞内钠，降低细胞内钾，抑制NCX以增加血小板钙储存和血小板反应性的假设。特异性目的3将检验高钾摄入降低细胞内钠、提高细胞内钾和刺激血小板NCX活性从而减少血小板钙储存和血小板反应性的假设。这个项目的发现可能会发现以前未知的饮食钠和钾对心血管的影响，从而揭示人类“盐敏感性”的新维度。

Recent work has demonstrated that the platelet Na/Ca exchanger (NCX) in human beings is identical to the retinal rod NCX. This exchanger plays an important role in regulating platelet Ca stores and it is driven not only by the Na electrochemical gradient but also by the K electrochemical gradient across the platelet plasma membrane. In addition, platelets express the alpha3 isoform of the Na-pump, an isoform with a heightened sensitivity to cardiac glycosides. These features of the platelet ion transport strongly link platelet Ca metabolism to fluctuations in systemic Na and K homeostasis and to the activity of the platelet Na-pump. At the core of this project is the hypothesis that the link between platelet Ca homeostasis and systemic Na/K regulation explains some cardiovascular effects of high Na and high K intakes that are independent of the effects of Na and K intakes on blood pressure. Three specific aims will explore this hypothesis. Specific Aim 1 will decipher the physiological and molecular characteristics of the Na-pump in human platelets, focusing on the alpha3 subunit isoform in these cells and its sensitivity to cardiac glycosides. The results will provide a better appreciation of the link between platelet NCX and the Na-pump. Specific Aim 2 will test the hypothesis that a high Na intake raises cytosolic Na, lowers cytosolic K, and inhibits the NCX to increase platelet Ca stores and platelet reactivity in human beings. Specific Aim 3 will test the hypothesis that a high K intake lowers cytosolic Na, raises cytosolic K and stimulates platelet NCX activity to diminish platelet Ca stores and platelet reactivity in human beings. Findings of this project might identify previously unknown cardiovascular effects of dietary Na and K, thereby revealing a new dimension of 'salt sensitivity' in human beings.