Allosteric Modulation of Neuronal Nicotinic Acetylcholine Receptors

神经元烟碱乙酰胆碱受体的变构调节

• 批准号: 8812153
• 负责人: Mark M Levandoski
• 金额: $ 41.47万
• 依托单位: GRINNELL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812153
• 关键词: Address; Agonist; Alzheimer' s Disease; Basic Science; Behavior; Binding; Binding Sites; Biochemistry; Chemicals; Chemosensitization; Communities; Cysteine; Development; Disease; Disulfides; Extracellular Domain; Face; Family; Foundations; Future; Gated Ion Channel; Goals; Head; Health; Human; Hydrophobic Interactions; Impaired cognition; Individual; Intervention; Investigation; Ion Channel; Ligand Binding; Ligands; Mediating; Modeling; Modification; Molecular; Movement; Neurons; Neuropharmacology; Neurophysiology - biologic function; Neurosciences; Nicotine Dependence; Nicotinic Receptors; Parkinson Disease; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Play; Point Mutation; Process; Property; Protein Family; Proteins; Relative (related person); Research; Role; Route; Science; Signal Transduction; Site; Specificity; Structure; Structure-Activity Relationship; Students; Testing; Therapeutic; Thermodynamics; Training; Work; analog; clinical application; cohort; crosslink; design; drug development; improved; innovation; mutant; nervous system disorder; novel; programs; protein structure; public health relevance; receptor; research study; voltage clamp

DESCRIPTION (provided by applicant): We study allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs). These ligand-gated ion channels are the seat of nicotine addiction and are implicated in a wide range of other neurological disorders. Allosteric modulation of nAChRs is growing in importance as it becomes better understood and as novel compounds with this pharmacological profile are identified. The binding sites for a class of model modulatory compounds, quite specific for one subtype of neuronal nAChR, are known, and some molecular determinants of transducing modulator binding information into channel activity have been identified. Building on this previous work, we now propose to further refine our understanding of the movement of one sub- structure involved in intra-molecular signal transduction and of the molecular determinants of modulator site specificity. In addition, questions about channel gating efficacy will be addressed in terms of the optimal number and arrangement of modulator sites relative to agonist sites and the role of hydrophobic residues in the extracellular domain core. These studies will employ pharmacological characterization of expressed receptors with point mutations or concatenated subunits by macroscopic voltage-clamp recordings, as well as chemical modification analyses. The project also includes a targeted structure-activity relationship study with new modulator analogues. In some cases, to support these primary aims, we will explore the modulation mechanisms further by single-channel recordings. Our work is innovative because we are challenging the paradigm of activation of nAChRs by occupying two agonist binding sites. We are studying a recently identified nAChR ligand binding site, and the work we propose stands to substantially strengthen the foundation for rational design of nAChR allosteric modulators, a drug class with possible clinical applications.

描述（由申请人提供）：我们研究神经元烟碱乙酰胆碱受体（nAChR）的变构调节。这些配体门控离子通道是尼古丁成瘾的根源，并与多种其他神经系统疾病有关。随着 nAChR 的变构调节得到更好的理解以及具有这种药理学特征的新化合物的被发现，它变得越来越重要。一类模型调节化合物的结合位点（对神经元 nAChR 的一种亚型非常特异）是已知的，并且已经鉴定了将调节剂结合信息转导为通道活性的一些分子决定因素。在先前工作的基础上，我们现在建议进一步完善我们对分子内信号转导所涉及的一个子结构的运动以及调节剂位点特异性的分子决定因素的理解。此外，有关通道门控功效的问题将根据调节剂位点相对于激动剂位点的最佳数量和排列以及胞外域核心中疏水残基的作用来解决。这些研究将通过宏观电压钳记录以及化学修饰分析，对具有点突变或串联亚基的表达受体进行药理学表征。该项目还包括利用新的调节剂类似物进行有针对性的结构-活性关系研究。在某些情况下，为了支持这些主要目标，我们将通过单通道录音进一步探索调制机制。我们的工作具有创新性，因为我们正在通过占据两个激动剂结合位点来挑战 nAChR 激活的范式。我们正在研究最近发现的 nAChR 配体结合位点，我们建议的工作将大大加强合理设计 nAChR 变构调节剂的基础，nAChR 变构调节剂是一类具有可能临床应用的药物。