Modulation of Nicotinic Receptors by Cytosolic Proteins

胞质蛋白对烟碱受体的调节

• 批准号: 7633281
• 负责人: Rene Anand
• 金额: $ 29.74万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633281
• 关键词: 14-3-3 Proteins; Addictive Behavior; Affinity; Alzheimer' s Disease; Axon; Axonal Transport; Binding Sites; Biogenesis; Biological; Brain; Calcium; Cell Line; Cell physiology; Cell surface; Cessation of life; Cholesterol; Cholinergic Receptors; Cysteine; Cytoplasmic Tail; Data; Endoplasmic Reticulum; Exhibits; Expenditure; Gated Ion Channel; Goals; Healthcare; Ion Channel; Laboratories; Lead; Ligands; Maps; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Molecular Chaperones; Neuraxis; Neurons; Nicotine; Nicotinic Receptors; Phosphorylation; Play; Property; Proteins; Publishing; Recruitment Activity; Research Personnel; Role; Schizoaffective Disorders; Site; Sphingolipids; Structure; Surface; Testing; Thalamic structure; Tobacco; Tobacco Dependence; Tobacco use; VSNL1 gene; addiction; base; brain cell; density; in vivo; mutant; nervous system disorder; novel; palmitoylation; presynaptic; programs; release of sequestered calcium ion into cytoplasm; research study; response; reticulum cell; sensor; stoichiometry; trafficking

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.

描述（由申请人提供）：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，可在烟草产物中介导对尼古丁的瘾。仅在美国，烟草使用造成灾难性的死亡人数（> 40万），与医疗保健相关的支出约为500亿美元。尼古丁对ACHR的重复激活可能首先会导致ACHR的结构，功能特性和细胞表面密度的根本变化。这些变化反过来促进了功能性神经元网络（例如中皮质胶体）的性质的长期自适应变化，从而介导了成瘾行为，从而导致烟草成瘾。我们的长期目标是了解调节ACHR的生物发生，结构，功能和细胞定位的生物学机制。在过去的几年中，我们的实验室已经确定了几种与alpha4beta2 aChR相互作用的新型胞质蛋白，这是一种在中枢神经系统中广泛表达的亚型，并与将尼古丁成瘾介导。该RO1提案的目标是测试有关alpha4beta2 aChR决定因素及其互补相互作用的特定假设，这些假设调节了alpha4beta2 achR相对于其1）stoichiimementry的生物发生； 2）轴突/树突靶； 3）聚类和4）细胞表面密度。这些假设基于广泛的新初步数据，以及与alpha4beta2 aChR相互作用的胞质蛋白相互作用的初始表征的发布结果。从这些研究中获得的结果将更好地理解调节alpha4beta2 ACHR结构，运输，分布和表面表达的可塑性的生物学机制。烟碱乙酰胆碱受体（ACHR）是脑细胞中介导烟草产物中成瘾的脑细胞中的离子通道。仅在美国，烟草的使用就会每年造成灾难性的死亡人数（> 400,000），与医疗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，并且其破坏可能在神经疾病（例如阿尔茨海默氏病和精神分裂症）中特别相关。