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首页> 外文学位 >Characterization of beta-arrestin/PAR2 interactions: Role of receptor modification and specific beta-arrestin family members in downstream signaling events.
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Characterization of beta-arrestin/PAR2 interactions: Role of receptor modification and specific beta-arrestin family members in downstream signaling events.

机译：β-arrestin/ PAR2相互作用的表征：受体修饰和特定的β-arrestin家族成员在下游信号事件中的作用。

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摘要

In recent times, GPCR signaling has been a major hotbed of research activity on account of the increasing use of GPCR's as therapeutic targets. Traditionally, GPCR signaling has focused mainly on the signaling propagated by the G-protein components. However, the situation is now being seen as becoming increasingly complex. A multitude of factors are now realized as playing a role in modulating GPCR functioning & signaling. Some of them like the different conformations that the seven transmembrane receptors can adopt when bound by agonists have propagated the pharmacological design of newer and better agonist or inhibitors. Other factors like the identification of different post translationally modified forms of the receptor have also sparked a variety of research activity in the importance of structural features of the receptor in influencing the downstream signals. In addition to all these factors the implications of the interactions of the GPCR's with their non-G-protein downstream effectors that can form a plethora of scaffolding complexes and mediate an independent arm of signaling is also being appreciated.; In this study, we focus on two areas that can modulate the behavior of a GPCR PAR2, which has been shown to be important in a variety of physiological processes. In the first part, we show the importance of beta-arrestins in modulating PAR2 functioning and show that the two individual isoforms of beta-arrestins can have very different effects on the internalization, desensitization and downstream activation of PAR2. These effects are shown to be different in a spatial, temporal as well as a kinetic pattern using a variety of biochemical and cell based approaches. In the second half of this work, we highlight the importance of the different post-translational modifications like phosphorylation (on the carboxyl-tail of the receptor) and glycosylation on the functioning of the receptor. We show that these receptor modifications have the potential to completely alter the signaling profiles of the receptors and thereby change the overall cellular and physiological response.; On the whole this study tries to clarify some of the parameters important in signaling of PAR2 that can be used further in the research for the usage of PAR2 as a therapeutic target.
机译：近年来，由于越来越多地使用GPCR作为治疗靶标，GPCR信号已成为研究活动的主要温床。传统上，GPCR信号转导主要集中在G蛋白成分传播的信号转导上。但是，现在情况变得越来越复杂。现在已经认识到许多因素在调节GPCR功能和信号传导中起作用。它们中的一些喜欢激动剂结合时七个跨膜受体可以采用的不同构象，从而传播了更新更好的激动剂或抑制剂的药理学设计。其他因素，如鉴定受体不同的翻译后修饰形式，也已引发了各种研究活动，说明了受体的结构特征在影响下游信号中的重要性。除所有这些因素外，人们还认识到GPCR与它们的非G蛋白下游效应子相互作用的意义，这种相互作用可以形成过多的支架复合物并介导独立的信号传导臂。在这项研究中，我们专注于可以调节GPCR PAR2行为的两个领域，这已显示在多种生理过程中很重要。在第一部分中，我们显示了β-arrestins在调节PAR2功能中的重要性，并显示了β-arrestin的两个同工型对PAR2的内在化，脱敏和下游活化具有非常不同的作用。使用各种基于生物化学和细胞的方法，这些效果在空间，时间和动力学模式上均显示出不同。在这项工作的后半部分，我们强调了不同的翻译后修饰的重要性，例如磷酸化（在受体的羧基尾部）和糖基化对受体的功能。我们表明，这些受体修饰具有完全改变受体信号传导谱的潜力，从而改变了总体细胞和生理反应。总体而言，本研究试图阐明一些对PAR2信号传导重要的参数，这些参数可以在研究中进一步用于将PAR2用作治疗靶标。

著录项

  • 作者

    Kumar, Puneet.;

  • 作者单位

    University of California, Riverside.;

  • 授予单位 University of California, Riverside.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 126 p.
  • 总页数 126
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

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