Different components of nicotine-induced upregulation of nicotinic receptors

尼古丁诱导烟碱受体上调的不同成分

• 批准号: 8584938
• 负责人: WILLIAM GREEN
• 金额: $ 46.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584938
• 关键词: Addictive Behavior; Address; Affect; Affinity; Area; Back; Binding; Biology; Brain; Bupropion; Bypass; Categories; Cell Culture Techniques; Cell surface; Cells; Cessation of life; Cigarette; Complex; Data; Development; Elements; Endocytosis; Endosomes; Enzymes; Esthesia; Exposure to; Galantamine; Glycoside Hydrolases; Goals; Golgi Apparatus; Health; Intervention; Ligands; Link; Mannose; Mediating; Modification; Molecular; Naltrexone; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Oligosaccharides; Pathway interactions; Pharmaceutical Preparations; Play; Polysaccharides; Positioning Attribute; Process; Proteins; Reagent; Recycling; Regulation; Research; Rewards; Role; Smoker; Structure; Testing; Time; Tobacco; Tobacco smoking; United States; Up-Regulation; Work; Zinc; addiction; base; cytisine; glycosylation; novel; prevent; reagent testing; receptor; receptor function; receptor recycling; receptor upregulation; research study; residence; smoking cessation; trafficking; varenicline

DESCRIPTION (provided by applicant): Tobacco smoking is a leading cause of preventable deaths in the United States and worldwide. Understanding why tobacco smoking is highly addictive and identifying the mechanisms underlying addiction would be of tremendous benefit in developing new therapies for smoking cessation needed for preventing addiction. Nicotine is the primary agent in tobacco leading to addiction. Addiction is initiated by nicotine binding to nicotinic acetylcholine receptors (nAChRs) in the brain. High-affinity nAChRs, mainly "¿4¿2" nAChRs in the brain's reward areas, mediate the reinforcing effects of nicotine. The only long-lasting effect, i.e., greater than a few minutes, of nicotine directly on nAChRs is a phenomenon called nicotine-induced upregulation of nAChRs (upregulation). We have demonstrated that nAChR upregulation is much more complex than originally assumed consisting of multiple processes that occur at very different rates and are caused by different mechanisms. One goal of the proposed research is to characterize in more detail the two components of nAChR upregulation that we have recently discovered. In the first Aim, we will examine how nicotine exposure increases nAChR endocytosis and recycling of ¿4¿2 nAChRs in neurons and heterologous cells. In the second Aim, we will test in more detail how nicotine exposure regulates the glycosylation of ¿4¿2 nAChRs. Another goal of the proposed research is to examine how nAChR ligands and smoking cessation agents affect the different components of upregulation. These experiments will be performed in the third Aim.

描述（由申请人提供）：吸烟是美国和全世界可预防死亡的主要原因。了解吸烟为何高度成瘾并确定成瘾的机制对于开发预防成瘾所需的新戒烟疗法将大有裨益。尼古丁是烟草中导致成瘾的主要物质。成瘾是由尼古丁与大脑中的烟碱乙酰胆碱受体（nAChR）结合引发的。高亲和力的 nAChR，主要是大脑奖励区域中的“¿4¿2”nAChR，介导尼古丁的增强作用。尼古丁直接对 nAChR 产生的唯一持久影响（即超过几分钟）是一种称为尼古丁诱导的 nAChR 上调（上调）的现象。我们已经证明，nAChR 上调比最初假设的要复杂得多，由多个过程组成，这些过程以非常不同的速率发生并由不同的机制引起。本研究的目标之一是更详细地描述我们最近发现的 nAChR 上调的两个组成部分。在第一个目标中，我们将研究尼古丁暴露如何增加 nAChR 内吞作用以及神经元和异源细胞中 4¿2 nAChR 的循环。在第二个目标中，我们将更详细地测试尼古丁暴露如何调节 4¿2 nAChR 的糖基化。拟议研究的另一个目标是检查 nAChR 配体和戒烟剂如何影响上调的不同组成部分。这些实验将在第三个目标中进行。