NEUROGENETICS OF BEHAVIOR

神经元和肌肉的可电兴奋细胞膜 对这些细胞进行纤化，以接收、处理和传输信息 在神经系统内。电的兴奋性被授予 通过称为通道的跨膜蛋白发挥关键作用 在动作电位传播和突触传递中通过 通过膜调节特定离子的流量。尽管 尽管最近取得了重要进展，但仍有许多悬而未决的问题 关于离子通道的结构、功能和调节。 这项工作的长期目标是阐明分子 膜兴奋性的基础机制是通过分离和 编码离子通道的基因突变的特征或 否则会影响它们的功能。本文件中描述的实验 建议重点关注三个突变：EAG(以太和棋)、贫民窟 (慢戳)和午睡(无动作电位)。我们已经证明了每一个 这些突变深刻地扰乱了膜的兴奋性 针对具体缺陷：EAG贬低了一类人的功能 钾通道；SLO完全取消了另一个 钾通道的一类；午睡减少了数量和/或功能 钠离子通道。然而，分子损伤是导致 这些缺陷目前还不清楚。突变可能会改变 编码经络或原因的结构成分的基因 一种细胞机制的扰动被认为是调节 通道活动或合成。遗传、电生理和 分子实验被用来阐明其根本原因。 这些突变体的缺陷。我们将完成EAG的克隆和 NAP，绘制这些基因座的分子界限图，识别它们的 转录，分离和测序cdna克隆，并使用 这些基因编码的蛋白质的特征信息。 我们将对SLO进行详细的细胞遗传学分析以分离出 新的等位基因，并给SLO一个精确的细胞学位置。 根据信息和由此产生的新突变体 对SLO的分子分析将通过染色体行走启动 或转座子标记。新的SLO等位基因将被描述为 以电生理来确定他们是否显示阵列 结构基因缺陷的表型。最后， 我们将通过继续筛查来识别新基因座的突变 对于(1)抑制或增强现有膜的突变 兴奋性突变或(2)表现出任何运动缺陷 如瘫痪或不协调。这些研究将提供新的 关于离子通道的结构和功能的信息以及 调节它们的合成、组装、膜的机制 插入、和调制。由于已知各种人类疾病 与离子函数中的微扰有关 渠道，我们在果蝇身上获得的信息应该是广泛的 具有生物学和医学意义。

The electrically excitable cell membrane of neurons and muscle fibers these cells to receive, process, and transmit information within the nervous system. Electrical excitability is conferred by transmembrane proteins called channels that play the key roles in action potential propagation and synaptic transmission by mediating fluxes of specific ions across the membrane. Despite important recent advances, many unanswered questions remain concerning the structure, function, and regulation of ion channels. The long term goal of this work is to elucidate the molecular mechanisms that underlie membrane excitability by isolating and characterizing mutations in genes that encode ion channels or that otherwise affect their function. Experiments described in this proposal focus on the three mutations: eag (ether a go-go), slo (slowpoke), and nap (no action potential). We have shown that each of these mutations profoundly disrupts membrane excitability owing to specific defects: eag diminishes the function of one class of potassium channels; slo entirely abolishes the function of another class of potassium channels; nap reduces the number and/or function of sodium channels. However, the molecular lesions responsible for these defects are not yet understood. The mutations could alter genes encoding structural components of channels or cause perturbations in one of the cellular mechanisms thought to regulate channel activity or synthesis. Genetic, electrophysiological, and molecular experiments are proposed to elucidate the underlying defects in these mutants. We will complete the cloning of eag and nap, map the molecular limits of these loci, identify their transcripts, isolate and sequences cDNA clones and use this information to characterize the proteins encoded by these genes. We will perform a detailed cytogenetic analysis of slo to isolate new alleles and to assign slo a precise cytological location. Based on the information and new mutants thus generated the molecular analysis of slo will be initiated by chromosome walking or transposon tagging. The new slo alleles will be characterized electrophysiologically to determine whether they display the array of phenotypes expected for defects in a structural gene. Finally, we will identify mutations at new loci by continuing our screens for mutations that (1) suppress or enhance existing membrane excitability mutations or (2) display any locomotor defects such as paralysis or uncoordination. These studies will provide new information on the structure and function of ion channels and on the mechanisms that regulate their synthesis, assembly, membrane insertion, nd modulation. Since various human disorder are known to be associated with perturbations in the function of ion channels, the information we obtain in Drosophila should have broad biological and medical significance.