The Neuronal alpha-bungarotoxin Binding Site

描述（由申请方提供）：神经元nAChR由许多亚型组成，根据其在中枢和外周神经系统中的不同药理学和分布进行分类。我们建议研究这样一个亚型，神经元α-银环蛇毒素结合受体（BgtR）在此授权申请。与其他离子型神经递质受体相比，BgtR是不寻常的，因为它们由单一亚基亚型，即17亚基组成。此外，17个亚基不能在大多数细胞中折叠和组装成BgtR，并且仅在正确的细胞环境中形成BgtR，主要在神经元中。因此，17个亚基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才能组装成BgtR。我们研究的总体目标是鉴定和表征参与BgtR表达的神经元特异性加工事件和蛋白质。在之前的资助期间，我们能够将蛋白质棕榈酰化鉴定为BgtR表达所需的神经元特异性翻译后修饰。我们还一直在表征一种神经元蛋白Ric-3，它也有助于介导BgtR表达。该建议的主要目的是表征亚基棕榈酰化和Ric-3在调节BgtR表达时BgtR异源表达或在神经元中表达的作用。具体来说，我们将确定棕榈酰化17个亚基的机制，测试17个亚基棕榈酰化的其他后果，确定Ric-3介导其对BgtR的影响的区域，并检查Ric-3如何改变翻译后加工17个亚基。公共卫生相关性：亲离子型神经递质受体是突触传递所必需的，并负责神经和肌肉中对神经递质的快速反应。在这个建议中，我们将研究一个特定的神经元烟碱乙酰胆碱受体（nAChR）亚型，1-银环蛇毒素结合受体（BgtR），这是一个离子型神经递质受体的表达的调节。作为尼古丁在大脑中结合的部位，这些受体负责尼古丁成瘾，并且在神经退行性疾病和精神疾病（如阿尔茨海默病和精神分裂症）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.