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首页> 外文学位 >The importance of subcellular localization of calcium(2+)/calmodulin-dependent protein kinase II in neuronal differentiation.
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The importance of subcellular localization of calcium(2+)/calmodulin-dependent protein kinase II in neuronal differentiation.

机译：钙（2 +）/钙调蛋白依赖性蛋白激酶II亚细胞定位在神经元分化中的重要性。

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摘要

Multiple influences guide the development of nerve cells from undifferentiated stem cells to fully functioning neurons. One influence in this process is the modulation of intracellular Ca2+ concentration, which signals through the enzyme Ca2+/Calmodulin dependent protein kinase II (CaMKII) to regulate a variety of cellular events. There are four isoforms of CaMKII, with numerous splice variants. At least three of these splice variants contain nuclear localization signals that direct the protein to the nucleus; the rest remain cytoplasmic or target to other subcellular locations. Cytoplasmic CaMKII has been implicated in several aspects of neuronal development, but little is known about the role of nuclear-localized CaMKII in this process. In order to understand the mechanisms controlling neuronal differentiation and neurite outgrowth, PC12 cells were transfected with transgenes coding for CaMKII, targeted to concentrate in either the cytoplasm or the nucleus. These cells were then treated with nerve growth factor (NGF) or cAMP.; When NGF binds to its receptor, it triggers a signaling cascade (MAPK) that ultimately results in the differentiation of PC12 cells into a neuronal phenotype, marked by extensive neurite outgrowth. This work found that PC12 cells expressing CaMKII in the nucleus failed to grow neurites in response to NGF, while cells expressing cytoplasmic CaMKII readily grew them. The inhibited neuronal differentiation was independent of MAPK activation, as sustained phosphorylation of Erk was not affected by the presence of either nuclear or cytoplasmic CaMKII. Nor did it arise from changes in phosphorylation of the transcription factor CREB, an important downstream mediator of NGF signaling.; PC12 cells also produce neurite-like processes in response to increasing intracellular cAMP. In contrast to NGF-induced neurites, the formation of cAMP-induced processes was not inhibited by nuclear CaMKII, but was inhibited by cytoplasmic CaMKII. The mechanisms by which cAMP and NGF stimulate their respective processes are believed to be different; cAMP is thought to work by causing rapid, transient rearrangements of the cytoskeleton while NGF induces neuronal differentiation. When applied simultaneously, NGF and cAMP have a synergistic affect on inducing neurite outgrowth. This synergism was seen in cell lines expressing either cytoplasmic or nuclear CaMKII, as well as control cells. Taken together, this data indicates that PC12 cells with nuclear CaMKII are capable of extending neurites, but the signaling mechanism for neuronal differentiation is blocked in a manner that can be compensated for by increasing intracellular cAMP.
机译：多种影响引导神经细胞从未分化的干细胞发展为功能全面的神经元。此过程中的一个影响因素是细胞内Ca 2 + 浓度的调节，该信号通过Ca 2 + /钙调蛋白依赖性蛋白激酶II（CaMKII）进行信号传递，从而调节多种事件的发生。 CaMKII有四种同工型，具有许多剪接变体。这些剪接变体中的至少三个包含将蛋白质定向到核的核定位信号。其余的保持细胞质或靶向其他亚细胞位置。细胞质CaMKII已牵涉到神经元发育的多个方面，但对核定位的CaMKII在此过程中的作用知之甚少。为了了解控制神经元分化和神经突向外生长的机制，将PC12细胞用编码CaMKII的转基因转染，靶向于浓缩在细胞质或细胞核中。然后用神经生长因子（NGF）或cAMP处理这些细胞。当NGF与其受体结合时，它会触发信号级联（MAPK），最终导致PC12细胞分化为神经元表型，并以广泛的神经突向外生长为标志。这项工作发现，在细胞核中表达CaMKII的PC12细胞不能响应NGF而生长神经突，而在表达细胞质CaMKII的细胞中却容易生长它们。抑制的神经元分化与MAPK激活无关，因为Erk的持续磷酸化不受核或细胞质CaMKII的存在的影响。它也不是由转录因子CREB的磷酸化变化引起的，CREB是NGF信号传导的重要下游介质。 PC12细胞还响应细胞内cAMP的增加而产生类似神经突的过程。与NGF诱导的神经突相反，cAMP诱导的过程的形成不受核CaMKII的抑制，但受细胞质CaMKII的抑制。人们认为，cAMP和NGF刺激其各自过程的机制是不同的。人们认为cAMP通过引起细胞骨架的快速，瞬时重排而起作用，而NGF则诱导神经元分化。当同时使用时，NGF和cAMP对诱导神经突生长具有协同作用。这种协同作用在表达细胞质或核CaMKII的细胞系以及对照细胞中可见。综上所述，该数据表明具有核CaMKII的PC12细胞能够延伸神经突，但是神经元分化的信号传导机制被阻断，可以通过增加细胞内cAMP来补偿。

著录项

  • 作者

    Kutcher, Louis Wm., III.;

  • 作者单位

    University of Cincinnati.;

  • 授予单位 University of Cincinnati.;
  • 学科 Biology Animal Physiology.; Biology Cell.; Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 124 p.
  • 总页数 124
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生理学;细胞生物学;神经科学;
  • 关键词

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