CENTRAL NICOTINIC CHANNEL KINETICS & SYNAPTIC FUNCTION

描述：(申请人摘要) 认知处理的神经机制很可能涉及 突触功能的调节。神经元乙酰胆碱受体(NAChRs) 一组与高级大脑功能有关的不同渠道 比如选择性注意力、学习和记忆。因为，特别是， NAChRs对细胞内信号钙离子具有不同的渗透性，这些 受体非常适合于促进多种持久的 细胞事件。为了了解nAChRs的作用，有必要了解 了解它们的分子特性。这项提议的目的是为了 深入了解： 中枢神经系统nAChRs受体组成和突触功能的研究 监管。 这些目标将通过检验两个具体的假设来实现： 1.选择在中枢神经系统核内起主导作用的nAChR亚型 我们认为大量的nAChR亚基是存在的，而不是形成一个巨大的 NAChR亚型的数量，但要创建一组基本的受体，每一种受体 具有最小的基本核心亚基。包含更多的亚基 将用来修改它们的基本功能。因此，我们可以预测，在某些地区 在存在大量nAChR亚单位的大脑中，某些类型的 主宰一切。 2.细胞内钙离子水平控制神经元nAChRs的敏感性 我们认为，nAChR的一个亚型的功能是对水平的感觉 通过调节细胞内钙离子对其递质的反应。因此， 它的功能可能会在持续的突触活动中得到增强。在……里面 转而，因为nAChRs允许钙离子进入细胞，它们将动态地贡献给细胞 细胞内钙信号转导。只要这种积极的反馈保持不变 受调控的nAChRs可能有助于突触的长期变化。如果 然而，这个过程变得不受调控，通过增加钙离子流量 增强的nAChR通道可导致细胞损伤。 通过解决这些假设，我们将能够提供神经机制 这可能是更高大脑功能的基础，并可能有助于解释 某些疾病中的胆碱能-尼古丁功能障碍。

DESCRIPTION: (Applicant's Abstract) Neuronal mechanisms that underlie cognitive processing are likely to involve modulation of synaptic function. Neuronal acetylcholine receptors (nAChRs) form a diverse group of channels that have been implicated in higher brain functions such as selective attention and learning and memory. Because, in particular, nAChRs are differentially permeable to the intracellular signal Ca2+, these receptors are ideally suited to contribute to a variety of long-lasting cellular events. In order to understand the role of nAChRs it is essential to understand their molecular properties. The goals of this proposal are to gain insight into: The synaptic functions of CNS nAChRs in terms of receptor composition and regulation. These aims will be addressed by testing two specific hypotheses: 1. Select nAChR subtypes serve dominant functions within CNS nuclei We suggest that the large number of nAChR subunits exist, not to form a vast number of nAChR subtypes, but to create a basic set of receptors, each of which has a minimal essential core of subunits. Inclusion of additional subunits would serve to modify their basic function. Thus we would predict that in areas of the brain where a large variety of nAChR subunits exist, certain types would dominate. 2. The level of intracellular Ca2+ controls the sensitivity of neuronal nAChRs We suggest that the function of one subtype of nAChR is to sense to the level of intracellular Ca2+ by adjusting its responsiveness to its transmitter. Thus, its function may be enhanced in the presence of ongoing synaptic activity. In turn, because nAChRs allow Ca2+ into cells they will contribute dynamically to intracellular Ca2+ signaling. Provided that this positive-feedback is kept regulated, nAChRs could contribute to long-lasting changes at synapses. If however, this process becomes unregulated, increased Ca2+ flux through potentiated nAChR channels could lead towards cell damage. By addressing these hypotheses, we will be able to offer neuronal mechanisms that could underlie higher brain functions and may help explain cholinergic-nicotinic dysfunction in certain diseases.