Regulation of Mu Opioid Receptor Signal Transduction

描述(申请人提供)：MU阿片受体(MOR)在许多功能中发挥重要作用，包括疼痛通路、呼吸系统、胃肠道活动控制、边缘(情绪)系统和奖励系统。他们是临床上重要药物的靶标，如吗啡和可待因。我们对MOR功能是如何调控的理解是不完整的。在初步研究中，我们发现在大鼠大脑发育过程中，MOR的功能发生了戏剧性的变化，比我们在研究其他神经递质系统时看到的任何变化都要大得多。这表明，这种发育范式将提供关于该系统内功能调节的新的和有趣的信息，这些信息不仅与成年动物的发育有关，而且与MOR功能有关。根据我们的初步数据，我们假设发育中的纹状体中MOR的组织和成熟的戏剧性变化是由与MOR相互作用的其他蛋白的表达变化所控制和调节的。具体目的1是研究G蛋白表达在MOR功能发育中的作用。这些研究包括分析与MOR相互作用的G蛋白亚型的发育表达，分析哪些特定的G蛋白亚型在发育的几个阶段与MOR相互作用，以及这些相互作用如何定量变化。具体目的2是研究MOR与其他蛋白的相互作用，这些蛋白可能在调节MOR的功能活动中发挥作用。这些研究最初集中在MOR与RanBPM的相互作用上，RanBPM是一种最初通过酵母双杂交筛选发现与MOR C末端尾巴相互作用的蛋白质。我们的初步数据支持这一假说，表明RanBPM调节MOR的信号转导功能。这一目的详细地研究了这种相互作用，分析了这两种蛋白质的哪些结构域对相互作用是重要的，并研究了RanBPM在发育过程中发现的MOR功能变化中的作用。我们认为，这些研究将提供有关在发育过程中调节MOR功能的重要信息，这些结果也将为深入了解成熟动物的MOR功能提供帮助。进一步了解MOR功能的调控不仅与MOR的发育有关，而且与涉及与MOR相互作用的药物的临床情况有关，如疼痛、腹泻和药物依赖。

DESCRIPTION (provided by applicant): Mu opioid receptors (MOR) play a major role in many functions, including pain pathways, the respiratory system, control of GI activity, the limbic (emotional) system and the reward system. They are the target of clinically important drugs, such as morphine and codeine. Our understanding of how MOR function is regulated is incomplete. In preliminary studies, we discovered dramatic changes in the function of MOR during the development of rat brain, changes far greater than any we have seen studying other neurotransmitter systems. This suggested that this developmental paradigm would provide novel and interesting information about regulation of function within this system, information relevant not only to development but also to MOR function in adult animals. Based upon our preliminary data, we hypothesize that the dramatic changes in organization and maturation of the MOR in developing striatum are governed and regulated by changes in the expression of other proteins interacting with MOR. Specific Aim 1 is to examine the role of G protein expression on the development of MOR function. These studies include analysis of the developmental expression of the G protein subtypes with which MOR interact, analysis of which specific G protein subtypes interact with MOR at several stages during development, and how these interactions change quantitatively. Specific Aim 2 is to examine the interaction of MOR with other proteins, which may play a role in regulating MOR functional activity. These studies initially focus on the interaction of MOR with RanBPM, a protein initially identified by yeast two-hybrid screen as interacting with the MOR C-terminal tail. Our preliminary data support this hypothesis, indicating RanBPM modulates the signal transduction functions of MOR. This aim examines this interaction in detail, analyzes which domains of these two proteins are important for the interaction, and investigates the role of RanBPM in the changes in MOR function found during development. We think these studies will provide important information about what regulates MOR function during development and that these results also will provide insight into MOR function in the mature animal. Further understanding of the regulation of MOR function is relevant not only to development but to clinical situations involving drugs interacting with MOR, such as pain, diarrhea and drug dependence.