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首页> 外文学位 >Extracellular nucleotide signaling in neuronal differentiation and survival: Multiple roles of the P2Y(2) receptor.
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Extracellular nucleotide signaling in neuronal differentiation and survival: Multiple roles of the P2Y(2) receptor.

机译：细胞外核苷酸信号传导神经元分化和生存：P2Y（2）受体的多重作用。

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摘要

Extracellular nucleotides signaling through P2 nucleotide receptors expressed throughout the nervous system regulate a variety of neuronal functions. The characterization of nucleotide effects on neuronal differentiation, growth and survival are potentially important targets that may facilitate regeneration and survival of neurons after injury, disease, or age-related loss of function. Work in this thesis tested the hypothesis that extracellular nucleotides, acting through P2 receptor(s), alter neuronal differentiation, growth and survival. I characterized morphological changes that occur with nerve growth factor (NGF) differentiation and corresponding changes in ATP release. Target tissues, such as vascular endothelial and cardiac cells, were identified as sources of ATP release and promoters of differentiation of PC12 cells independent of NGF. The altered expression of P2X and P2Y receptors in differentiated versus non-differentiated PC12 cells, combined with the enhancement of NGF-stimulated differentiation by ATP and UTP led to the identification of P2Y2 receptors as mediating nucleotide-promoted neuronal differentiation and growth in primary cultured neurons and PC12 cells. Such effects occurred via increased NGF sensitivity and enhanced activation of the NGF receptor, TrkA. Endogenous co-localization and co-immunoprecipitation of P2Y2 and TrkA receptors requiring activated Src as a physical intermediate. In vivo treatment with ATPgammaS treatment enhanced a marker of neuronal growth. P2Y2 receptor activation, independent of NGF/TrkA, also mediated inhibition of neuronal apoptosis by ATP/UTP. In addition to effects on differentiation, P2Y2 inhibition of apoptosis occurred through Src-mediated activation of ERK and Akt. In other experiments I found that undifferentiated, compared to NGF-differentiated, PC12 cells had lower, briefer ATPgammaS-stimulated norepinephrine release and reuptake; only NGF-differentiated PC12 cells were capable of desensitization to ATPgammaS. These results identify a role for P2Y2 receptors in neurotrophin-dependent differentiation as well as neurotrophin-independent inhibition of neuronal apoptosis. P2Y 2 receptors thus regulate neuronal differentiation, survival, and function in part via interaction with neurotrophin/receptor tyrosine kinase receptors. As such, P2Y2 receptors provide a new target for therapeutic intervention in neuropathological conditions.
机译：通过在整个神经系统中表达的P2核苷酸受体发出信号的细胞外核苷酸调节各种神经元功能。核苷酸对神经元分化，生长和存活的影响的表征是潜在的重要靶标，可促进损伤，疾病或与年龄相关的功能丧失后神经元的再生和存活。本论文的工作检验了一种假设，即通过P2受体起作用的细胞外核苷酸会改变神经元的分化，生长和存活。我描述了随着神经生长因子（NGF）分化而发生的形态变化以及相应的ATP释放变化。目标组织，例如血管内皮细胞和心肌细胞，被确定为ATP释放的来源和PC12细胞独立于NGF分化的促进剂。 P2X和P2Y受体在分化PC12和未分化PC12细胞中表达的改变，再加上ATP和UTP增强NGF刺激的分化，导致P2Y2受体被鉴定为介导核苷酸促进的神经元分化和原代培养神经元的生长。和PC12电池。这种作用是通过增加NGF敏感性和增强NGF受体TrkA的激活而发生的。 P2Y2和TrkA受体的内源性共定位和共免疫沉淀需要激活的Src作为物理中间体。 ATPgammaS治疗的体内治疗增强了神经元生长的标志物。 P2Y2受体激活，独立于NGF / TrkA，也通过ATP / UTP介导神经元凋亡的抑制。除了对分化的影响外，P2Y2对细胞凋亡的抑制作用还通过Src介导的ERK和Akt激活而发生。在其他实验中，我发现与NGF分化相比，未分化的PC12细胞具有更低，更短的ATPgammaS刺激的去甲肾上腺素释放和再摄取的能力。只有NGF分化的PC12细胞能够对ATPgammaS脱敏。这些结果确定了P2Y2受体在神经营养蛋白依赖性分化以及神经营养蛋白依赖性神经元凋亡抑制中的作用。因此，P2Y 2受体部分地通过与神经营养蛋白/受体酪氨酸激酶受体的相互作用来调节神经元的分化，存活和功能。这样，P2Y2受体为神经病理学状况的治疗干预提供了新的靶点。

著录项

  • 作者

    Arthur, David Benjamin.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 177 p.
  • 总页数 177
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;
  • 关键词

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