SUBUNIT SPECIFIC REGULATION OF NICOTINIC RECEPTORS

描述(申请人摘要)： 为什么神经性尼古丁受体(NAChRs)在结构上包含这样一个 不同类型的配基门控离子通道尚不清楚。然而，很可能 反映了它们在突触调节和调节中的不同作用 在整个神经系统中传播。NAChRs被牵连到 学习和记忆、慢性成瘾和神经退行性疾病--所有这些 其中受调节nAChR功能的因素影响较大。因此， 更好地了解特定的nAChRs参与这些活动 过程可以通过确定 烟碱型乙酰胆碱受体(NAChR)及其短期和长期 注册。在成瘾的框架内，这项提案解决了 NAChRs亚基组成与其功能的关系这个 具体目标将指向但不限于，回答 问题是：nAChR脱敏是必要的也是充分的 解释以下观察到的nAChR数量和功能的变化 长期接触尼古丁？这一目标将通过审查nAChRs来实现 在各种表达系统中的已知亚基组成。这项研究将 重点关注尼古丁在与烟草相关的浓度下的相互作用， 对于nAChR子类型，其属性与其在 中枢神经系统(CNS)。它将为 以下三个假设：(1)nAChRs的功能性质可以是 从它们的亚基组成预测。激活和脱敏 我们将研究nAChRs的特征，认为某些 亚基将赋予受体显性特性。(2)生化 受体特性的调节是以nAChR亚型特有的方式发生的。 个别亚基将不同地服从于其他 细胞因素(例如，钙离子和磷酸化)。(3)结果 NAChRs对尼古丁的长期暴露将与功能性 特性和特定的nAChRs的生化状态。一个完整的 对nAChRs亚基特异性属性的理解将预测如何 中枢神经系统中不同的nAChR应在长期的条件下受到影响 暴露于烟草相关浓度的尼古丁。这些数据将 建议哪些类型的受体可能在成瘾中起重要作用 进程。除了解决与神经生物学相关的问题外， 成瘾，这些研究将提供对亚单位的进一步洞察 中枢神经系统中nAChRs的组成和调控。总体而言，这些知识 将是重要的，不仅对于有选择性和潜在的设计 治疗剂，但也是为了理解为什么只有一类 受体应该具有如此多样化的分子基础。

DESCRIPTION (Applicant's Abstract): Why neuronal nicotinic receptors (nAChRs) comprise such a structurally diverse group of ligand-gated ion channels is unknown. However, it likely reflects their diverse roles in both the modulation and mediation o synaptic transmission throughout the nervous system. nAChRs have been implicated in learning and memory, chronic addiction and neurodegenerative diseases - all of which will be influenced by factors which regulate nAChR function. Thus, a greater understanding of the participation of particular nAChRs in these processe could be achieved by determining the link between the subtype of nicotinic acetylcholine receptor (nAChR) and its short and long-term regrulation. Within the framework of addiction, this proposal addresses the relationship between subunit composition of nAChRs and their function. The specific aims will be directed towards although not limited to, answering the question: Is nAChR desensitization both necessary and sufficient to explain the alterations in nAChR number and function observed following chronic exposure to nicotine? This aim will be pursued by examining nAChRs of known subunit composition in various expression systems. The study will focus on the interaction of nicotine, at tobacco-related concentrations, with nAChR subtypes the have properties consistent with their presence in the central nervous system (CNS). It will provide evidence for the following three hypotheses: (1) The functional properties of nAChRs can be predicted from thei subunit composition. The activation and desensitization characteristics of nAChRs will be examined with the idea that certain subunits will confer dominant properties upon receptors. (2) Biochemical regulation o receptor properties occurs in a nAChR subtype-specific manner. Individual subunits will be differentially amenable to regulation by other cellular factors (e.g., Ca2+ and phosphorylation). (3) The outcome o prolonged exposure of nAChRs to nicotine will be related to the functional propeffies and the biochemical state of particular nAChRs. A full understanding of the subunit-specific properties of nAChRs will predict how different nAChRs in the CNS should be affected under conditions of long-term exposure to tobacco-related concentrations of nicotine. Such data will suggest which types of receptors are likely to be important in the addiction process. In addition to addressing issues related to the neurobiology of addiction, these studies will provide further insights into the subunit composition and regulation of nAChRs in the CNS. Overall, this knowledge will be important, not only for the design of selective and potentially therapeutic agents, but also for understanding why a single class of receptors should have such a diverse molecular basis.