Modulation of Nicotinic Receptors by Cytosolic Proteins

描述(申请人提供)：烟碱型乙酰胆碱受体(AChRs)是中枢神经系统中的配体门控离子通道，调节烟草产品中对尼古丁的上瘾。仅在美国，烟草使用每年就造成灾难性的死亡人数(40万英镑)，与医疗保健相关的支出约为500亿美元。尼古丁对AChRs的反复激活可能首先导致AChRs的结构、功能特性和细胞表面密度发生根本变化。这些变化反过来又会导致功能性神经网络(如中皮质边缘神经网络)特性的长期适应性变化，这些神经网络介导成瘾行为，从而导致烟草成瘾。我们的长期目标是了解调节AChRs的生物发生、结构、功能和细胞定位的生物学机制。在过去的几年里，我们的实验室已经发现了几种新的胞浆蛋白，它们与α4beta2 AChR相互作用，Alpha4beta2AChR是一个在中枢神经系统中广泛表达的亚型，与尼古丁成瘾有关。这项RO1提案的目的是测试关于α4beta2 AChR决定因素及其互补相互作用的特定假设，这些因素从1)化学计量学；2)轴突/树突靶向；3)聚集和4)细胞表面密度调节α4beta2 AChR的生物发生。这些假说基于大量新的初步数据，以及对与α4beta2 AChR相互作用的胞浆蛋白相互作用的初步表征的出版结果。这些研究结果将有助于更好地理解调控α4β2 AChR可塑性的生物学机制，包括结构、运输、分布和表面表达。烟碱型乙酰胆碱受体(AChRs)是脑细胞中的离子通道，介导对烟草产品中尼古丁的上瘾。仅在美国，烟草使用每年就导致灾难性的死亡人数(40万英镑)，与医疗保健相关的支出约为500亿美元。拟议研究的结果将更好地理解导致烟草成瘾的生物学机制，这种机制的破坏可能与阿尔茨海默病和分裂情感障碍等神经疾病特别相关。

DESCRIPTION (provided by applicant): Nicotinic acetylcholine receptors (AChRs) are ligand-gated ion channels in the central nervous system that mediate addiction to nicotine in tobacco products. Tobacco use is responsible for a catastrophic number of deaths (>400,000) per year in the U.S. alone and a health care-related expenditure of approximately $50 billion. It is likely that repetitive activation of AChRs by nicotine first leads to fundamental changes in the structure, functional properties and cell surface density of AChRs. These changes, in turn, drive long-term adaptive changes in the properties of functional neuronal networks (e.g. mesocorticolimbic) that mediate addictive behaviors and thus lead to tobacco addiction. Our long-term goal is to understand the biological mechanisms that regulate the biogenesis, structure, functions and cellular localization of AChRs. Over the last few years, our laboratory has identified several novel cytosolic proteins that interact with the alpha4beta2 AChR, a subtype that is widely expressed in the central nervous system and implicated in mediating addiction to nicotine. The objectives of this RO1 proposal are to test specific hypotheses about alpha4beta2 AChR determinants and their complementary interactors that regulate the biogenesis of the alpha4beta2 AChRs with respect to their 1) stoichiometry; 2) axonal/dendritic targeting; 3) clustering and 4) cell surface density. These hypotheses are based on extensive new preliminary data, as well as published results of the initial characterization of the interaction of cytosolic proteins that interact with alpha4beta2 AChR. The results obtained from these studies will provide a better understanding of the biological mechanisms that regulate plasticity in alpha4beta2 AChR structure, transport, distribution and surface expression. Nicotinic acetylcholine receptors (AChRs) are ion channels in brain cells that mediate addiction to nicotine in tobacco products. Tobacco use causes a catastrophic number of deaths (>400,000) per year in the U.S. alone and a health care-related expenditure of approximately $50 billion. The results obtained from the proposed studies will provide a better understanding of biological mechanisms that lead to tobacco addiction and whose disruption may be particularly relevant in neurological diseases such as Alzheimer's disease and schizoaffective disorders.