SUBUNIT SPECIFIC REGULATION OF NICOTINIC RECEPTORS

描述（申请人摘要）： 为什么神经元烟碱受体（nAChRs）在结构上包含这样的结构， 不同的配体门控离子通道组是未知的。 然而，它可能 反映了它们在突触的调节和介导中的不同作用。 通过神经系统传播。 nAChR与 学习和记忆，慢性成瘾和神经退行性疾病-所有 其中，nAChR的功能受调节因子的影响。 因此，在本发明中， 更好地了解特定nAChR参与这些 可以通过确定 烟碱型乙酰胆碱受体（nAChR）及其短、长时程 再调节。 在成瘾问题的框架内，这项建议涉及 nAChRs的亚基组成与其功能之间的关系。 的 具体目标将针对，但不限于，回答 问题：nAChR脱敏是否既必要又充分， 解释以下观察到的nAChR数量和功能的变化 长期接触尼古丁 这一目标将通过检查nAChRs来实现 已知的亚基组成在不同的表达系统。 这项研究将 重点是尼古丁的相互作用，在烟草相关的浓度， nAChR亚型具有与它们在 中枢神经系统（CNS）。 它将提供证据， 以下三个假设：（1）nAChR的功能特性可以是 从它们的亚基组成预测。 激活和脱敏 nAChRs的特性将被检查的想法，某些 亚基将赋予受体优势性质。 (2)生化 受体性质的调节以nAChR亚型特异性方式发生。 单个亚基将不同地服从于其他亚基的调节。 细胞因子（例如，Ca 2+和磷酸化）。 (3)结果O nAChR长期暴露于尼古丁将与功能性 和特定nAChRs的生化状态。 全 了解nAChRs的亚单位特异性特性将预测如何 CNS中的不同nAChR应在长期 暴露于与烟草相关的尼古丁浓度。 这些数据将 提示哪些类型的受体可能在成瘾中起重要作用 过程 除了解决与神经生物学相关的问题外， 成瘾，这些研究将提供进一步的见解亚基 在CNS中的nAChR的组成和调节。 总的来说，这些知识 将是重要的，不仅对设计的选择性和潜在的 治疗药物，但也为了理解为什么一个单一的类 受体应该具有如此多样的分子基础。

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.