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The Neuronal alpha-bungarotoxin Binding Site

神经元 α-银环蛇毒素结合位点

基本信息

批准号：
8305585
负责人：
WILLIAM GREEN
金额：
$ 33.89万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305585
关键词：
Address Affect Affinity Alzheimer&apos s Disease Applications Grants Binding Biogenesis Biological Assay Brain Bungarotoxins Caenorhabditis elegans Cell Line Cell surface Cells Cholinesterase Inhibitors Cysteine Data Disease Dominant-Negative Mutation Elements Endoplasmic Reticulum Environment Enzymes Event Family Funding Genetic Screening Goals Golgi Apparatus Grant Hippocampus (Brain)Ion Channel Laboratories Lead Life Link Measurement Mediating Membrane Membrane Microdomains Mental disorders Molecular Chaperones Muscle Mutagenesis Nerve Nervous system structure Neurodegenerative Disorders Neurons Neurotransmitter Receptor Neurotransmitters Nicotine Nicotine Dependence Nicotinic Receptors PC12 Cells Peripheral Nervous System Pharmacology Phosphorylation Play Post-Translational Protein Processing Process Proline Property Proteins Rattus Regulation Research Resistance Role Schizophrenia Site Surface Synaptic Transmission System Techniques Testing Tissues Transferase United States National Institutes of Health alpha-bungarotoxin receptor glycosylation in vivo interest member mutant neurotrophic factor palmitoylation receptor receptor binding receptor expression research study response stoichiometry trafficking

项目摘要

Neuronal nAChRs are composed of a number of subtypes as classified by their diverse pharmacology and distribution in the central and peripheral nervous system. We propose to study one such subtype, the neuronal a-bungarotoxin binding receptor (BgtR) in this grant application. BgtRs are unusual compared to other ionotropic neurotransmitter receptors in that they composed of single subunit subtype, the ¿7 subunit. Additionally, ¿7 subunits fail to fold and assemble into BgtRs in most cells and only form BgtRs in the correct cellular environment, mainly in neurons. Thus, ¿7 subunits require one or more neuronal-specific processing events or neuronal-specific proteins in order to assemble into BgtRs. The overall goal of our research has been to identify and characterize the neuronal-specific processing events and proteins involved in BgtR expression. In the previous funding period, we were able to identify protein palmitoylation as a neuronal-specific posttranslational modification required for BgtR expression. We also have been characterizing a neuronal protein, Ric-3, that also helps mediate BgtR expression. The main objective of this proposal is to characterize the roles of subunit palmitoylation and Ric-3 in regulating BgtR expression when BgtRs are expressed heterologously or in neurons. Specifically, we will be identifying the machinery that palmitoylates ¿7 subunits, testing for additional consequences of ¿7 subunit palmitoylation, determining region of Ric-3 mediating its effects on BgtRs and examining how Ric-3 alters the posttranslational processing ¿7 subunits. Ionotropic neurotransmitter receptors are essential for synaptic transmission and are responsible for the rapid responses to neurotransmitters in nerve and muscle. In this proposal, we will study the regulation of the expression of a specific neuronal nicotinic acetylcholine receptor (nAChR) subtype, the ¿-bungarotoxin binding receptor (BgtR), which is an ionotropic neurotransmitter receptor. As the site where nicotine binds in the brain, these receptors are responsible for nicotine addiction and also play a role in neurodegenerative and psychiatric diseases such as Alzheimers disease and schizophrenia.

神经元nAChR由许多亚型组成，如根据它们的多样性分类的。药理学和在中枢和外周神经系统中的分布。我们建议研究其中一种亚型，神经元α-银环蛇毒素结合受体（BgtR）在这份资助申请中与其他离子型相比，BgtR是不寻常的神经递质受体，因为它们由单个亚单位亚型组成，即由7 亚单位此外，在大多数细胞中，7个亚基不能折叠和组装成BgtR，只有在正确的细胞环境中才能形成BgtR，主要是在神经元中。因此，<$7个子单位需要一个或多个神经元特异性加工事件或神经元特异性蛋白质，组装成BgtR。我们研究的总体目标是确定和表征参与BgtR的神经元特异性加工事件和蛋白质表情在上一个资助期，我们能够识别蛋白质，棕榈酰化作为BgtR所需的神经元特异性翻译后修饰表情我们还研究了一种神经元蛋白Ric-3，介导BgtR表达。本提案的主要目的是描述亚基棕榈酰化和Ric-3在调节BgtR表达中的作用，异源表达或在神经元中表达。具体来说，我们将确定棕榈酰化<$7亚基的机器，测试<$7的额外后果亚基棕榈酰化，Ric-3的决定区介导其对BgtR的作用，研究Ric-3如何改变翻译后加工的7个亚基。离子型神经递质受体是突触传递所必需的，负责对神经和肌肉中的神经递质做出快速反应。在这建议，我们将研究一个特定的神经元烟碱表达的调节乙酰胆碱受体（nAChR）亚型，银环蛇毒素结合受体（BgtR），其是离子型神经递质受体。因为尼古丁结合在大脑中，这些受体负责尼古丁成瘾，也在神经变性和精神疾病，如阿尔茨海默病，精神分裂症