CENTRAL NICOTINIC CHANNEL KINETICS & SYNAPTIC FUNCTION

描述：（申请人摘要） 认知过程的神经元机制可能涉及 突触功能的调节。神经元乙酰胆碱受体（nAChRs）形式 一组与高级大脑功能有关的不同的通道 比如选择性注意力和学习记忆。因为，特别是， nAChR对细胞内信号Ca 2+的渗透性不同，这些 受体非常适合于促进各种持久的 细胞事件为了了解nAChRs的作用， 了解它们的分子特性。该提案的目标是获得 深入了解： CNS nAChR在受体组成和突触功能方面的作用 调控 这些目标将通过检验两个具体假设来解决： 1.选择nAChR亚型在CNS核内发挥主导功能 我们认为，大量的nAChR亚单位存在，而不是形成一个巨大的， 许多nAChR亚型，但要创建一组基本的受体，每一个 有一个最小的基本核心的亚基。增加次级单位 会改变它们的基本功能因此，我们可以预测， 在存在大量nAChR亚基的大脑中，某些类型的nAChR亚基 主宰 2.细胞内Ca 2+水平控制神经元nAChRs的敏感性 我们认为nAChR的一种亚型的功能是感知水平， 通过调节其对递质的反应性来调节细胞内Ca 2+。因此，在本发明中， 其功能可以在存在进行中的突触活动的情况下增强。在 反过来，因为nAChRs允许Ca 2+进入细胞，它们将动态地促进 细胞内Ca 2+信号传导。只要保持这种正反馈， 如果nAChR受到调节，则nAChR可能有助于突触的持久变化。如果 然而，这一过程变得不受调节，增加的Ca 2+通量通过 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， 这可能是大脑高级功能的基础，也可能有助于解释 某些疾病中的胆碱能-烟碱功能障碍。

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.