BINDING SITE STRUCTURE OF NEURONAL NICOTINIC RECEPTORS

神经型烟碱型乙酰胆碱受体(NAChRs)是人们非常感兴趣的 因为它们是乙酰胆碱必须作用于兴奋的关键部位 前脑。这些受体特别令人感兴趣，因为它们 尼古丁发挥其精神活性和成瘾作用的部位。 对神经元nAChRs的药物干预有望用于治疗 中枢神经系统疾病的影响 理解和治疗上瘾的过程。一个特别重要的问题 治疗靶点是nAChRs与乙酰胆碱结合的部位。 不幸的是，我们对此的结构性基础的理解 互动是有限的。此外，为了使治疗剂有效，他们 必须能够区分多个功能子类型 神经系统中存在的nAChRs。研究项目 我在本申请中所描述的将识别特定的氨基酸 决定药物药理特性的残留物 神经元nAChRs的神经递质结合部位。实验性的 策略是利用这个成员之间的药理差异 受体家族作为受体结构的探针。这将使用以下工具完成 分子生物学技术。嵌合受体亚单位将是 通过将一个亚基的特定序列片段替换为 药理上不同的亚基的相似序列片段。 通过测定形成的受体的药理学特性 嵌合亚单位，决定药理作用的序列片段 特异性将被确定。根据这些研究的结果 实验中，单个氨基酸之间会发生变化 药理上截然不同的受体。这些实验将确定 决定药理特异性的特定氨基酸。这个 这些实验的结果将有助于治疗剂的设计 对单个受体亚型有选择性。具体药物将是 在治疗和探索尼古丁的机制方面有很大的用处 上瘾。

Neuronal nicotinic acetylcholine receptors (nAChRs) are of great interest because they are critical sites at which acetylcholine must act to excite the forebrain. These receptors are of particular interest because they are the sites at which nicotine exerts its psychoactive and addictive effects. Pharmacologic intervention at neuronal nAChRs holds promise for treating the effects of diseases of the central nervous system and for understanding and treating addictive processes. A particularly important therapeutic target is the site at which nAChRs bind acetylcholine. Unfortunately, our understanding of the structural basis for this interaction is limited. Also, for therapeutic agents to be effective, they must be capable of distinguishing among the multiple functional subtypes of nAChRs that are present in the nervous system. The research project that I describe in this application will identify the specific amino acid residues that determine the pharmacological properties of the neurotransmitter binding sites of neuronal nAChRs. The experimental strategy is to use the pharmacological differences between members of this receptor family as probes of receptor structure. This will be done using the techniques of molecular biology. Chimeric receptor subunits will be constructed by replacing specific sequence segments of one subunit with the analogous sequence segment of a pharmacologically distinct subunit. By determining the pharmacological properties of receptors formed by chimeric subunits, the sequence segments that determine pharmacological specificity will be identified. Drawing on the results of these experiments, individual amino acid changes will be made between pharmacologically distinct receptors. These experiments will identify the specific amino acids that determine pharmacological specificity. The results of these experiments will aid in the design of therapeutic agents selective for individual receptor subtypes. Specific drugs will be of great use in treating, as well as probing the mechanism of, nicotine addiction.