The Neuronal alpha-bungarotoxin Binding Site

描述（由申请人提供）：突触传递的中心是离子型神经递质受体家族，其负责对神经和肌肉中的神经递质的快速反应。在这个建议中，一类受体，是这个家庭的成员，神经元烟碱受体，将进行研究。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，也可能在阿尔茨海默病等神经退行性疾病中发挥作用。神经元AChR由许多亚型组成，根据其不同的药理学和分布进行分类。一个这样的亚型，神经元α-银环蛇毒素结合受体（BgtR）将在这项授权进行研究。我们已经发现BgtR仅由烟碱α 7亚基组成，并且α 7 BgtR的功能性表达仅发生在神经元来源的细胞中。第一个目标是鉴定和表征BgtR表达所需的神经元特异性加工。以神经元特异性方式调节BgtR表达的翻译后事件的鉴定应提供对其他受体和通道如何调节的见解。另一个目的是确定BgtR上Bgt结合位点的数量，并开始表征BgtR Ab肽结合位点。在阿尔茨海默病的发病中起关键作用的Ab肽与BgtR结合，改变BgtR功能并触发神经元内的第二信使变化。待检验的假设是：1）a7亚基棕榈酰化是功能性BgtR表达所需的一系列加工事件之一; 2）每个BgtR上有四个配体结合位点，并且这些位点可以通过对拮抗剂的不同亲和力来区分;和3）Ab肽结合BgtR细胞外表面上不同于配体结合位点的位点。

DESCRIPTION (provided by applicant): Central to synaptic transmission are the family of ionotropic neurotransmitter receptors, which are responsible for the rapid responses to neurotransmitters in nerve and muscle. In this proposal, a class of receptors that are members of this family, the neuronal nicotinic receptors, will be studied. As the site where nicotine binds in the brain, these receptors are responsible for nicotine addiction and may also play a role in neurodegenerative diseases such as Alzheimer's disease. Neuronal AChRs are composed of a number of subtypes as classified by their diverse pharmacology and distribution. One such subtype, the neuronal a-bungarotoxin binding receptor (BgtR) will be studied in this grant. We have found that that BgtRs are composed only of nicotinic a7 subunits and functional expression of a7 BgtRs only occurs in cells of neuronal origin. The first objective is to identify and characterize the neuronal-specific processing required for BgtR expression. The identification of posttranslational events that regulate BgtR expression in a neuronal-specific manner should provide insights into how other receptors and channels are regulated. The other objective is to determine the number of Bgt binding sites on BgtRs and to begin to characterize the BgtR Ab peptide binding sites. Ab peptides, which are play a critical role in the onset of Alzheimer's disease, bind to BgtRs, altering BgtR function and trigger second messenger changes within neurons. The hypotheses to be tested are that: 1) a7 subunit palmitoylation is one of a series of processing events required for expression of functional BgtRs; 2) there are four ligand binding sites on each BgtR and the sites can be distinguished by different affinities for antagonists; and 3) Ab peptides bind to a site on the BgtR extracellular surface different from the ligand binding sites.