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首页> 外文学位 >The roles of lithium(+), magnesium(2+), and sodium ions in bipolar disorder and essential hypertension: A multinuclear NMR and fluorescence study
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The roles of lithium(+), magnesium(2+), and sodium ions in bipolar disorder and essential hypertension: A multinuclear NMR and fluorescence study

机译：锂（+），镁（2+）和钠离子在躁郁症和原发性高血压中的作用：多核NMR和荧光研究

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摘要

Li+ is the primary drug to treat bipolar disorder, however, its exact mechanism of action is unknown. Guanine nucleotide-binding (G) proteins are involved in signal transduction, and therefore, much effort has been given to elucidate their role in bipolar disorder. Because these proteins are Mg 2+ dependent, the Li+/Mg2+ competition hypothesis with respect to binding and activation was explored with a G-protein, rGialpha1, and two of its mutants (T181D and T181V). Using fluorescence spectroscopy and 7Li NMR relaxation rates, we found that ion competition did occur in the three forms of rGialpha1, as well as significantly decreased Mg2+ binding and activation in one of the mutant forms, T181V.;Although Li+ decreases the number of episodes associated with bipolar disorder, some patients do not respond to treatment, while others become toxic. Therefore, it would be valuable to determine whether the patient will respond or become toxic to Li+ prior to treatment. Through 7Li and 31P NMR spectroscopy, and AA (atomic absorption) spectrophotometry, we determined Li+ transport and binding values, phospholipid composition, and intracellular [Mg2+] f in red blood cells (RBCs) from 30 Li+-treated bipolar patients and found that at least one of these biochemical variables has a strong predictive value in determining response and toxicity.;The cytoskeleton is a feature of the RBC that supports the cytoplasmic face. To determine whether the loss of the cytoskeleton enhances ion binding and competition for membrane binding sites, we used unsealed and cytoskeleton-depleted RBC membrane samples in conjunction with 7Li NMR relaxation rates. We observed an increase in Li+ binding and ion competition in cytoskeleton-depleted membrane samples, which indicates that phospholipid head groups as well as membrane proteins contribute toward Li+ binding in the RBC membrane.;G-proteins regulate ion transport, and may provide insight into hypertension. Abnormal function of certain G-proteins may be the cause of irregularities in Na+ transport, which is often seen with this disease. By fluorescence and 23Na+ NMR spectroscopy, we found that Na+ readily competes for Mg2+-binding sites in rGialpha1 and affects the activity of the protein. These findings support the theory that in hypertensive patients the functioning of G-proteins is altered. Hypertensive patients also display alterations in intracellular [Mg2+]f levels when compared to normotensives. Upon treatment with antihypertensive medication, these levels were similar to normotensives. Intracellular [Mg2+]f, phospholipid composition, and Na+ transport and binding in RBCs from 15 treated and 4 untreated essential hypertensives were studied using 23Na+ and 31P NMR spectroscopy, and AA spectrophotometry. This study sought to determine if treatment with antihypertensive medication would correct alterations in these biochemical parameters. No definitive conclusions can be drawn from the hypertension study because of the difficulty in obtaining blood samples from untreated hypertensives, and thus the resulting small sample size.
机译：Li +是治疗躁郁症的主要药物，但是其确切的作用机理尚不清楚。鸟嘌呤核苷酸结合（G）蛋白参与信号转导，因此，人们已经做出很多努力来阐明它们在躁郁症中的作用。由于这些蛋白质是Mg 2+依赖性的，因此我们利用G蛋白rGialpha1及其两个突变体（T181D和T181V）探索了关于结合和激活的Li + / Mg2 +竞争假设。使用荧光光谱法和7Li NMR弛豫率，我们发现离子竞争确实发生在三种形式的rGialpha1中，并且显着降低了突变形式之一T181V中Mg2 +的结合和激活；尽管Li +减少了相关的发作次数患有双相情感障碍的患者中，有些患者对治疗无反应，而另一些患者中毒。因此，在治疗前确定患者是否会对Li +产生反应或变得有毒将是有价值的。通过7Li和31P NMR光谱，以及AA（原子吸收）分光光度法，我们确定了来自30名接受Li +治疗的双相患者的红细胞（RBC）中的Li +转运和结合值，磷脂成分以及细胞内[Mg2 +] f，并发现这些生化变量中的至少一个在确定反应和毒性方面具有很强的预测价值。细胞骨架是支持细胞质面孔的RBC的特征。为了确定细胞骨架的丢失是否增强离子结合和对膜结合位点的竞争，我们结合7Li NMR弛豫率使用未密封和细胞骨架耗尽的RBC膜样品。我们观察到在细胞骨架耗尽的膜样品中Li +结合和离子竞争增加，这表明磷脂头基和膜蛋白有助于RBC膜中的Li +结合; G蛋白调节离子运输，并可能提供深入了解高血压。某些G蛋白的功能异常可能是Na +转运异常的原因，这种疾病经常可见。通过荧光和23Na + NMR光谱，我们发现Na +容易竞争rGialpha1中的Mg2 +结合位点，并影响蛋白质的活性。这些发现支持了在高血压患者中G蛋白功能发生改变的理论。与正常血压相比，高血压患者的细胞内[Mg2 +] f水平也有变化。用降压药治疗后，这些水平与血压正常者相似。使用23Na +和31P NMR光谱法和AA分光光度法研究了15种已治疗和4种未治疗原发性高血压患者红细胞中的细胞内[Mg2 +] f，磷脂成分以及Na +的运输和结合。这项研究试图确定用降压药治疗是否可以纠正这些生化参数的改变。由于难以从未经治疗的高血压患者中获取血液样本，从而导致样本量小，因此无法从高血压研究中得出明确的结论。

著录项

  • 作者

    Williams, Nicole Marie.;

  • 作者单位

    Loyola University Chicago.;

  • 授予单位 Loyola University Chicago.;
  • 学科 Biochemistry.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 152 p.
  • 总页数 152
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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