HOMOMERIC NICOTINIC ACETYLCHOLINE RECEPTORS

描述：（改编自研究者摘要）： 本项目旨在阐明烟碱的结构和功能特征， 含有α 7、α 8或α 9亚基（α 7-、α 8-或α 9-）的乙酰胆碱受体 a9-nAChR）。a7、a8和a9是最古老的nAChR亚基， 它们被假定创造的复合体也许是最简单的形式 的nAChR。然而，这些nAChR，特别是α 7-nAChR， 经典兴奋性神经传递的介质。他们也可以玩小说 作为神经递质释放调节剂的生理作用，神经突 生长，甚至神经元死亡/存活。a7-nAChR也与 在神经系统的发育、分化和疾病中， 烟草尼古丁作用的目标。该项目是建立在前期工作 证明这些亚基在天然的细胞中作为同源nAChR表达， nAChR缺失的人上皮细胞系SH-EP 1及其惊人的特性 这些nAChR的野生型和突变型。 该项目的具体目标是（1）产生和表征突变体 识别尼古丁作为功能性拮抗剂的α 7-nAChR形式，（2） 产生并表征截短的α 7 nAChR的功能形式，（3）以 确定含有α 7亚基的nAChR是否也能组装成异聚体 以及这种异聚体α 7-nAChR是否具有独特的性质，以及（4） 表征α 8-nAChR和α 9-nACh R的异源表达形式。这些 研究将检验假设，即选择的配体结合和/或 nAChR的通道衬里结构域影响药物是否作为激动剂或 对手。他们将检验截短形式的nAChR 亚基可以被工程化以仍然保留组装为 配体结合功能性离子通道。该项目还将测试 假设α 7亚基仅作为同源体组装。它将阐明nAChR 当在相同的细胞环境中表达时， 环境影响nAChR的表达。计划中的研究将有助于 揭示了对配体识别、组装和 nACh R.该项目的发现与我们的理解有关 nAChR在神经系统功能和疾病中发挥的重要作用 和尼古丁依赖。

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.