K-DEPENDENT NA/CA EXCHANGE IN HUMAN PLATELETS

最近的研究表明，人类的血小板Na/Ca交换器(NCX)与视网膜视杆细胞的NCX是相同的。这种交换器在调节血小板钙储存方面起着重要作用，它不仅受Na电化学梯度的驱动，也受跨越血小板质膜的K电化学梯度的驱动。此外，血小板表达钠泵的α3亚型，这是一种对心脏糖苷类化合物高度敏感的亚型。血小板离子转运的这些特征将血小板钙代谢与全身钠钾稳态的波动和血小板钠泵的活性紧密地联系在一起。这个项目的核心假设是，血小板钙稳态和全身Na/K调节之间的联系解释了高Na和高K摄入量对心血管的一些影响，这些效应与Na和K摄入量对血压的影响无关。三个具体目标将探讨这一假说。具体目标1将破译人类血小板钠泵的生理和分子特征，重点是这些细胞中的α3亚单位亚基异构体及其对心脏糖苷类化合物的敏感性。这一结果将对血小板NCX和钠泵之间的联系提供更好的认识。特定目标2将验证这样的假设，即高钠摄入增加了人体内细胞内Na，降低了细胞内K，并抑制了NCX增加血小板钙储备和血小板反应性。特定目标3将验证这样的假设，即高K摄入量会降低细胞内Na，升高细胞内K，并刺激血小板NCx活性，从而减少人类的血小板钙储备和血小板反应性。这一项目的发现可能会确认此前未知的饮食钠和钾对心血管的影响，从而揭示人类对盐敏感的一个新维度。

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.