The Neuronal alpha-bungarotoxin Binding Site

描述(由申请人提供)：神经元nAChRs由许多亚型组成，根据其不同的药理作用和在中枢和外周神经系统中的分布进行分类。我们建议研究一个这样的亚型，神经元a-银环蛇毒素结合受体(BgtR)在这个赠款应用。与其他离子型神经递质受体相比，BgtR是不寻常的，因为它们由单一的亚基亚型组成，即17亚基。此外，在大多数细胞中，17个亚基不能折叠和组装成BgtR，而只在正确的细胞环境中形成BgtR，主要是在神经元中。因此，17个亚基需要一个或多个神经元特异性处理事件或神经元特异性蛋白才能组装成Bgtr。我们研究的总体目标是识别和表征参与BgtR表达的神经元特异性处理事件和蛋白质。在之前的资助时期，我们能够确定蛋白质棕榈酰化是BgtR表达所需的神经元特异性翻译后修饰。我们还鉴定了一种神经元蛋白Ric-3，它也有助于介导BgtR的表达。本研究的主要目的是研究当BgtRs异源表达或在神经元中表达时，亚基棕榈酰化和Ric-3在调节BgtR表达中的作用。具体地说，我们将确定使17个亚基棕榈酰化的机制，测试17个亚基棕榈酰化的额外后果，确定Ric-3介导其对BgtRs影响的区域，并研究Ric-3如何改变翻译后加工17个亚基。公共卫生相关性：离子型神经递质受体对突触传递至关重要，并负责对神经和肌肉中的神经递质做出快速反应。在这项研究中，我们将研究一种特殊的神经元烟碱型乙酰胆碱受体(NAChR)亚型--1-银环蛇毒素结合受体(BgtR)的表达调节，它是一种亲离子神经递质受体。作为尼古丁在大脑中的结合部位，这些受体与尼古丁成瘾有关，也在阿尔茨海默病和精神分裂症等神经退行性疾病和精神疾病中发挥作用。

DESCRIPTION (provided by applicant): 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 17 subunit. Additionally, 17 subunits fail to fold and assemble into BgtRs in most cells and only form BgtRs in the correct cellular environment, mainly in neurons. Thus, 17 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 17 subunits, testing for additional consequences of 17 subunit palmitoylation, determining region of Ric-3 mediating its effects on BgtRs and examining how Ric-3 alters the posttranslational processing 17 subunits. PUBLIC HEALTH RELEVANCE: 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 1-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.