Modulation of Nicotinic Receptors by Cytosolic Proteins

描述（由申请方提供）：烟碱乙酰胆碱受体（AChR）是中枢神经系统中的配体门控离子通道，介导烟草制品中尼古丁成瘾。仅在美国，烟草使用每年就造成灾难性的死亡人数（> 40万人），以及约500亿美元的医疗保健相关支出。尼古丁对乙酰胆碱受体的重复激活可能首先导致乙酰胆碱受体的结构、功能特性和细胞表面密度发生根本性变化。这些变化，反过来，驱动功能神经元网络（如mesocorticolimbic）的特性的长期适应性变化，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，我们的实验室已经确定了几种新的胞质蛋白，与α 4 β 2 AChR相互作用，这是一种在中枢神经系统中广泛表达的亚型，并参与介导尼古丁成瘾。该RO 1提案的目的是测试关于α 4 β 2 AChR决定簇及其互补相互作用物的特定假设，所述互补相互作用物调节α 4 β 2 AChR的生物发生，关于其1）化学计量; 2）轴突/树突靶向; 3）聚类和4）细胞表面密度。这些假设是基于广泛的新的初步数据，以及公布的结果的初步表征的相互作用的胞质蛋白质与α 4 β 2乙酰胆碱受体。从这些研究中获得的结果将提供一个更好的理解的生物学机制，调节可塑性的α 4 β 2乙酰胆碱受体的结构，运输，分布和表面表达。尼古丁乙酰胆碱受体（AChR）是脑细胞中的离子通道，介导对烟草产品中尼古丁的成瘾。仅在美国，烟草使用每年就导致灾难性的死亡人数（> 40万人），以及约500亿美元的医疗保健相关支出。从拟议的研究中获得的结果将使人们更好地了解导致烟草成瘾的生物学机制，其中断可能与阿尔茨海默病和情感障碍等神经系统疾病特别相关。

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.