Regulation of alpha7 nAChRs and NACHO

苏珊，秋田 项目摘要 烟碱型乙酰胆碱受体(NAChRs)参与多种生理过程，包括 运动活动对复杂的大脑功能，包括学习/记忆功能和注意力。NAChRs也有 已被证明介导内稳态突触可塑性(HSP)，这是一种稳定神经活动的保护机制。 因此，nAChRs的功能障碍或缺失与多种神经系统疾病有关。例如, α7nAChR与阿尔茨海默病、尼古丁成瘾、尼古丁诱发的癫痫等疾病有关 作为精神分裂症。事实上，增强nAChR信号是治疗多发性多发性硬化的一种长期有效的方法。 神经精神/病理障碍。尽管这一点很重要，但仍有许多事情需要了解 NAChRs被组装并运输到神经元的质膜上，特别是当神经元遇到 活动的变化。拟议的研究集中在Nacho，一种新发现的内质网(ER)-- 驻留蛋白，被证明是客户特有的nAChRs伴侣，对于贩运α7nAChRs是必不可少的。 我们在果蝇中使用分子遗传学方法来克服研究细胞内的一些限制 哺乳动物神经元中的α7nAChRs。我们：1)研究了nacho和α7nAChR up的时间关系- 热休克过程中的调节，2)热休克过程中nacho和α7是否相互依赖，以及一个是否 足以上调另一个，以及3)研究α7和Nacho在ER/Gogli中的本地化如何 HSP过程中的变化。

Tsunoda, Susan Project Summary Nicotinic acetylcholine receptors (nAChRs) are involved in a wide range of physiological processes, from motor activity to complex brain functions, including learning/memory function and attention. nAChRs have also been shown to mediate homeostatic synaptic plasticity (HSP), a protective mechanism stabilizing neural activity. As such, dysfunction or loss of nAChRs has been implicated in a variety of neurological diseases. For example, the α7 nAChR has been implicated in Alzheimer’s Disease, nicotine addiction, nicotine-induced seizures, as well as schizophrenia. Indeed, enhancing nAChR signaling is a long-validated approach to treating multiple neuropsychiatric/pathological disorders. Despite this importance, much remains to be understood about how nAChRs are assembled and trafficked to the plasma membrane in neurons, especially when neurons encounter changes in activity. The proposed studies focus on NACHO, a newly identified endoplasmic reticulum (ER)- resident protein, shown to be a client-specific chaperone of nAChRs, and essential for trafficking α7 nAChRs. We use molecular-genetic approaches in Drosophila to overcome some of the limitations of studying intracellular α7 nAChRs in mammalian neurons. We: 1) examine the temporal relationship of NACHO and α7 nAChR up- regulation during HSP, 2) test whether NACHO and α7 depend on one another during HSP and whether one is sufficient to up-regulate the other, and 3) examine how the localization of α7 and NACHO in the ER/Gogli changes during HSP.