Daily Regulation of Ionic Currents

 描述（由申请人提供）：昼夜节律是人体生理学的一个基本方面。昼夜节律的破坏是一个重大的健康负担，影响睡眠，心血管，代谢和精神疾病。了解身体生理的昼夜节律调节如何有助于人类健康和疾病，需要对昼夜节律如何产生和表达有基本的了解。这项研究的总体目标是确定编码大脑生物钟视交叉上核（SCN）昼夜节律的基本机制。SCN回路在动作电位（AP）放电中经历同步的每日振荡，并且昼夜行为和生理特征由该SCN回路节律建立。离子通道活性的日常调节是SCN中神经元活性产生昼夜节律的关键基础。在这种离子通道中，BK钙和电压激活的钾通道（Kcnma 1）是昼夜节律的中枢调节器。BK电流幅度的日常调制驱动SCN回路节律性，并且BK通道功能的丧失破坏昼夜行为和生理节律。BK电流水平的昼夜差异是由β2亚基介导的，这导致BK通道在白天失活。基于β2功能的BK电流特性的昼夜变化是独特的，但β2如何调节AP活性以塑造SCN神经元活动的节律尚不清楚。所提出的研究检验了以下假设：β2介导的失活是BK通道在SCN AP放电中的动态作用所需的关键性质，并且该过程是昼夜节律行为的核心。将使用急性SCN脑切片中BK电流和AP的电生理学记录研究该假设，提供数据以将AP波形变化与β2亚基的失活特性相关联。此外，BK电流的失活的后果，源于BK的钙源的昼夜变化将进行调查。最后，将检测人类癫痫连锁突变和其他改变BK/β2电流特性的单核苷酸多态性（SNP）的影响，并确定与SCN和行为节律性的相关性。该项目的结果将是对BK电流的日常调节如何控制SCN兴奋性的理解，为影响人类BK通道活性的机制提供新的生理和翻译见解。

 DESCRIPTION (provided by applicant): Circadian rhythmicity is a fundamental aspect of human physiology. Disruption of circadian rhythm is a significant health burden, impacting sleep, cardiovascular, metabolic and psychiatric disorders. Understanding how circadian modulation of the body's physiology contributes to human health and disease requires a basic understanding of how circadian rhythms are generated and expressed. The overall goal of the proposed research is to identify the basic mechanisms of that encode circadian rhythmicity in the suprachiasmatic nucleus (SCN), the brain's clock. The SCN circuit undergoes synchronized daily oscillations in action potential (AP) firing, and circadian behavioral and physiological characteristics are established by this SCN circuit rhythm. Daily modulation of ion channel activity is a critical basis for generating the circadian rhythm in neuronal activity in the SCN. Oe such ion channel, the BK calcium- and voltage-activated potassium channel (Kcnma1) is a central regulator of circadian rhythm. Daily modulation of BK current magnitude drives SCN circuit rhythmicity, and loss of BK channel function disrupts circadian behavioral and physiological rhythms. The day-night difference in BK current level is mediated by the β2 subunit, which causes inactivation of BK channels during the day. The circadian variation in BK current properties based on β2 function is unique, but it is not clear how β2 regulates AP activiy to shape the rhythms in SCN neuronal activity. The proposed studies test the hypothesis that β2-mediated inactivation is the critical property required for the BK channel's dynamic role in SCN AP firing, and that this process is central to circadian behavior. This hypothesis will be investigated using electrophysiological recordings of BK currents and APs in acute SCN brain slices, providing data to correlate changes in AP waveforms with inactivating properties of the β2 subunit. Furthermore, the consequences for inactivation of BK currents that stem from circadian changes in BK's calcium source will be investigated. Lastly, the impact of a human epilepsy-linked mutation and other single nucleotide polymorphisms (SNPs) that vary BK/β2 current properties will be tested and the relevance to SCN and behavioral rhythmicity will be determined. The outcome of this project will be an understanding of how the daily regulation of BK currents governs SCN excitability, providing new physiological and translational insight into the mechanisms that influence human BK channel activity.