Modulation of Nicotinic Receptors by Cytosolic Proteins

描述（由申请人提供）：尼古丁乙酰胆碱受体（achr）是中枢神经系统中的配体门控离子通道，介导烟草制品中的尼古丁成瘾。仅在美国，烟草使用每年就造成了灾难性的死亡人数（100万至40万人），并造成了大约500亿美元的医疗保健相关支出。很可能是尼古丁对achr的重复激活首先导致achr的结构、功能特性和细胞表面密度发生根本性的变化。这些变化反过来又推动调节成瘾行为的功能性神经网络（如中皮质边缘）特性的长期适应性变化，从而导致烟草成瘾。我们的长期目标是了解调控achr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与alpha4beta2 AChR相互作用的新型细胞质蛋白，alpha4beta2 AChR是一种在中枢神经系统中广泛表达的亚型，与介导尼古丁成瘾有关。本RO1提案的目的是测试关于alpha4beta2 AChR决定因子及其互补相互作用因子的特定假设，这些相互作用因子调节alpha4beta2 AChR的生物发生，涉及它们的1)化学计量；2)轴突/树突靶向；3)集群和4)细胞表面密度。这些假设是基于广泛的新的初步数据，以及与alpha4beta2 AChR相互作用的细胞质蛋白相互作用的初步表征结果。这些研究结果将有助于更好地理解调控alpha4beta2 AChR结构、转运、分布和表面表达可塑性的生物学机制。烟碱乙酰胆碱受体（achr）是介导烟草制品中尼古丁成瘾的脑细胞离子通道。仅在美国，烟草使用每年就造成了灾难性的死亡人数（100万至40万人），与卫生保健相关的支出约为500亿美元。从拟议的研究中获得的结果将更好地了解导致烟草成瘾的生物学机制，其破坏可能与阿尔茨海默病和精神分裂情感性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.