Function of the Novel Ion Channel narrow abdomen in Daily Rhythms

描述（由申请人提供）：日常节律紊乱与多种脑部疾病有关。这些节律至少由两种相互交织的途径调节，一种是生物钟，另一种是调节对光反应活动的掩蔽途径。该建议利用果蝇（Drosophila melanogaster）来解决这些途径。昼夜节律和掩蔽功能的遗传基础似乎是保守的，这表明在果蝇中的发现将广泛适用。一个神秘而高度保守的离子通道窄腹（na）在昼夜节律输出和掩蔽调节中都起着关键作用。这些观察结果奠定了本提案的总体目标，即在行为、神经元和分子水平上提供na在掩蔽和昼夜节律中的功能的综合观点。本建议的具体目的是：1。绘制na功能的神经基质图。NA可能在昼夜节律起搏器神经元中起调节掩蔽行为的作用。组织特异性救援和NA分布的评估将被执行，以解决NA在昼夜节律和感光神经元中的功能。还将检查时钟和/或光对NA的调节。2. 目的：明确na突变神经元的电生理表型。已经开发出一种方法来检查果蝇起搏器神经元的电特性。这些关键神经元中离子电流的表征，na对这些电流的影响，以及难以捉摸的na通道本身的电生理特性将被检查，包括生物钟和/或光的调节。3. 评估NA通道特性改变的后果。NA是电压门控阳离子通道家族中独特而保守的成员。NA揭示了离子通道的许多特征，包括高度保守的孔选择性和电压传感器序列。改变孔隙或电压传感器序列的NA通道的功能将通过行为救援进行测试。总之，这些研究将在与昼夜节律和掩蔽调节相关的不同解剖途径中定义NA的电生理功能。鉴于时钟和NA的守恒，这一建议应该阐明人类的日常节律及其对疾病的贡献。

DESCRIPTION (provided by applicant): Disturbed daily rhythms have been implicated in a variety of brain disorders. These rhythms are regulated by at least two intertwined pathways, one is the circadian clock and a second is the masking pathway that mediates activity in response to light. This proposal addresses these pathways using the fruit fly, Drosophila melanogaster. The genetic basis of circadian and masking function appears conserved, suggesting that findings in the fly will be widely applicable. A critical role for an enigmatic and highly conserved ion channel narrow abdomen (na) has been identified in both circadian output and masking regulation. These observations underlie the overall goal of this proposal, which is to provide an integrated view of na function in both masking and circadian rhythms at the behavioral, neuronal, and molecular levels. The specific aims of this proposal are: 1. To map the neural substrates of na function. NA may function in circadian pacemaker neurons to regulate masking behavior. Tissue-specific rescue and assessments of NA distribution will be performed to address NA function in circadian and photoreceptor neurons. The regulation of NA by the clock and/or light will also be examined. 2. To define the electrophysiological phenotype of na mutant neurons. A method has been developed to examine the electrical properties of Drosophila pacemaker neurons. Characterization of ionic currents in these key neurons, the effects of na on these currents, as well as the electrophysiological properties of the elusive NA channel itself will be examined, including regulation by the circadian clock and/or light. 3. To assess the consequences of altered NA channel properties. NA is a unique and conserved member of the voltage-gated cation channel family. NA reveals many signatures of ion channels including highly conserved pore selectivity and voltage sensor sequences. The function of NA channels with altered pore or voltage sensor sequences will be tested by behavioral rescue. In total, these studies will define the electrophysiological function of NA within distinct anatomic pathways relevant to circadian and masking regulation. Given the conservation of clocks and NA, this proposal should illuminate human daily rhythms and their contribution to disease.