HOMOMERIC NICOTINIC ACETYLCHOLINE RECEPTORS

描述：(改编自《调查员摘要》)： 本项目旨在阐明烟碱的结构和功能特征。 含有A7或8或9亚基的乙酰胆碱受体(A7-、A8-或 A9-nAChR)。A7、A8和A9是最古老的nAChR亚基，而同分体 他们被假定创造的复合体可能是最简单的形式 NAChR.然而，这些nAChR，特别是A7-nAChR广泛存在 经典兴奋性神经传递的介体。他们也可以玩小说 神经递质释放的生理调节作用，轴突 生长，甚至神经元的死亡/存活。A7-nAChR也被牵连 神经系统的发育、分化和疾病 烟草尼古丁作用的靶标。该项目是在前期工作中立项的 证明这些亚基在天然中以同源nAChR的形式表达 NAChR缺失的人上皮细胞系SH-EP1及其惊人特性 这些nAChR的野生型和突变型。 该项目的具体目标是(1)产生和鉴定突变株 识别尼古丁为功能性拮抗剂的A7-nAChR形式，(2)至 生成并刻画截断a7nAChR的函数形式，(3)to 确定含有oc7亚基的nAChR是否也可以作为异构体组装 以及这种异构体A7-nAChR是否具有独特的性质，以及(4) 鉴定a8nAChR和a9-nach R的异源表达形式 研究将检验配体结合和/或选择突变(S)的假设 NAChR的通道衬里结构域影响药物是作为激动剂还是 对抗者。他们将测试截断形式的nAChR的假设 亚基可以被设计成仍然保持组装为 配体结合，功能离子通道。该项目还将测试 假设A7亚基只以同源异构体的形式组装。它将阐明nAChR 在相同的细胞环境中表达时的功能以及是否/如何细胞 环境影响nAChR的表达。计划中的研究将有助于 揭示对配基识别、组装和 NACH R的功能在项目中的发现与我们的理解相关 NAChR在神经系统功能和疾病中的重要作用 以及尼古丁依赖。

DESCRIPTION: (Adapted from the Investigator's Abstract): The long-term goal of this project is to elucidate structural and functional features of nicotinic acetylcholine receptors containing a7, or8 or or9 subunits (a7-, a8-, or a9-nAChR). a7, a8 and a9 are the most ancient nAChR subunits, and the homomeric complexes that they are postulated to create are perhaps the most simple form of nAChR. Nevertheless, these nAChR, particularly a7-nAChR, are widespread mediators of classical excitatory neurotransmission. They also may play novel physiological roles as modulators of neurotransmitter release, neurite outgrowth, and even neuronal death/survival. a7-nAChR also have been implicated in development, differentiation, and disease of the nervous system and are targets of tobacco nicotine action. The project is founded in preliminary work demonstrating expression of these subunits as homomeric nAChR in the native nAChR-null human epithelial cell line SH-EP1 and revealing startling properties of wild-type and mutant forms of these nAChR. The specific aims of the project are (1) to generate and characterize mutant forms of a7-nAChR that recognize nicotine as a functional antagonist, (2) to generate and characterize functional forms of truncated a7nAChR, (3) to ascertain whether nAChR containing oc7 subunits can also assemble as heteromers and whether such heteromeric a7-nAChR have distinctive properties, and (4) to characterize heterologously expressed forms of a8nAChR and a9-nACh R. These studies will test hypotheses that selected mutation(s) of ligand binding and/or channel lining domains of nAChR influence whether drugs act as agonists or antagonists. They will test the hypothesis that truncated forms of nAChR subunits can be engineered to nevertheless retain abilities to assemble as ligand-binding, functional ion channels. The project will also test the hypothesis that a7 subunits only assemble as homomers. It will elucidate nAChR function when expressed in the same cellular environment and whether/how ceil environment influences expression of nAChR. The planned studies will help to reveal structural features critical to ligand recognition, assembly, and function of nACh R. Findings in the project are relevant to our understanding of the important roles played by nAChR in nervous system function and disease and in nicotine dependence.