CELLULAR CA2+ ION HOMEOSTASIS AND THE IMPACT OF AGING

该项目是对机制的调查， 细胞实现胞质游离Ca2+的稳态 浓度（（Ca2+）c），并允许扰动（Ca2+）c在 对激素和神经递质的反应。 此外，它 解决了这些控制机制中的紊乱， 发生在老年。 今年，我们提出了以下要求 问题. (1)激素的作用机制是什么 胰高血糖素导致肝细胞内（Ca 2+）c升高？ 的 环腺苷酸类似物提高（Ca 2+）c的功效， 对胰高血糖素OD变化的类似剂量反应， 丙酮酸激酶活性的变化， 通过蛋白激酶A磷酸化，已经向我们表明， 仅涉及蛋白激酶A的机制是足够的，尽管 不能排除其他机制。 (2)什么膜 载体蛋白参与介导Ca2+进入 肌细胞的细胞周期变化 这 化合物增强Na+通道活性，并导致大的 （Ca 2+）c增加，我们发现这种效应是有用的 工具，模拟高工作量，为我们的代谢研究， 肌细胞 我们试图区分 钙通道和Na +/Ca2+交换的抑制剂 维拉帕米、尼群地平、Cd 2+和二氯苯扎明， 得到的答案表明，这两个贡献， 细胞外Na+、H+和Na +-H +-Na + Ca2+浓度和去极化程度。 (3)是 有不同的α-和β-肾上腺素能作用， 去极化诱导的CA 2+进入心肌细胞？ 我们 研究了装载有Quin-2的细胞，并发现了一种新的 相互作用，使得Ca2+通量被β- 激动剂单独使用比α-和β-激动剂一起使用更有效。 (4)是 在蛋白质磷酸化水平上， 先前描述的CA 2+转运反应性降低 对衰老心脏中的儿茶酚胺有什么影响吗 我们已经确定了一 衰老心肌细胞中肌钙蛋白磷酸化水平降低 老鼠，目前正专注于受磷蛋白。

This project constitutes an investigation into mechanisms whereby cells achieve the homeostasis of cytosolic free Ca2+ concentrations ((Ca2+)c), and allow perturbations in (Ca2+)c in response to hormones and neurotransmitters. Further, it addresses derangements in these control mechanisms which may occur in old-age. This year, we have asked the following questions. (1) What is the mechanism whereby the hormone glucagon leads to and increase in (Ca2+)c in hepatocytes? The efficacy of cyclic-AMP analogues in raising (Ca2+)c and the similar dose-response to glucagon od changes in (ca2+)c and changes in the activity of pyruvate kinase, which is phosphorylated by protein kinase A, have suggested to us that a mechanism involving solely protein kinase A is sufficient, though other mechanisms cannot be excluded. (2) What membrane carrier proteins are involved in mediating the entry of Ca2+ into myocytes when they are treated with veratridine? This compound potentiates Na+-channel activity and leads to a large increase in (Ca2+)c, an effect which we have found to be a useful tool in simulating a high work-load for our metabolic studies in myocytes. We have sought to distinguish between an involvement of Ca2+ channels and Na+/Ca2+ exchange by using the inhibitors verapamil, nitrendipine, Cd2+ and dichlorobenzamil, and have obtained answers indicating that the contribution of these two processes to total flux varies with the extracellular Na+, H+ and Ca2+ concentrations and the degree of depolarization. (3) Are there distinct alpha- and beta-adrenergic effects on the depolarization-induced entry of CA2+ into cardiac myocytes? We have studied cells loaded with Quin-2 and have identified a novel interaction, such that Ca2+ flux is activated more by beta- agonists alone than by alpha- and beta-agonists together. (4) Are there correlates at the level of protein phosphorylation of the previously described decreased responsiveness of CA2+ transport to catecholamines in the aging heart? We have identified a decreased phosphorylation of troponin in myocytes from senescent rats and are currently focusing on phospholamban.