Daily Regulation of Ionic Currents

摘要 生理上的昼夜节律对人类健康是必不可少的，而在哺乳动物中，这些 节律由位于视交叉上区的中央生物钟协调。 下丘脑的核(SCN)。SCN产生昼夜节律的神经编码 时间通过依赖于一天中的时间的各种离子通道的活动的调制 控制动作电位触发。这项研究的目的是了解离子通道 设置这些昼夜节律变化的属性、交互作用和功能结果 SCN中的动作电位活动，集中在两种类型的功能上的通道 相互作用过程中的动作电位：BK钾通道及其钙通道激活剂。 在SCN的白天，BK通道主要由L型钙通道激活 在夜间，激活依赖于Ryanodine受体(RyR)。这是怎么回事 这两种钙通道亚型之间的切换尚不清楚，但有重要意义 在任何BK通道利用多个细胞的动作电位期间的暗示 Ca2+来源。拟议中的研究验证了BK活动的调节通过 特定的钙通道偶联改变BK通道对该作用的贡献 潜力。这种改变功能耦合的昼夜节律后果将 与钙离子通道突变以及与以下相关的BK通道突变有关 与KCNMA1相关的神经疾病--通道病。我们的具体目标是：(1) 确定BK和BK之间的关键亚基以及物理和功能相互作用 利用生物化学和生物化学技术调节SCN昼夜放电的钙通道 电生理学。破坏这些相互作用对昼夜节律的影响 节律将在SCN电路和昼夜行为输出中进行评估，以及(2) 确定致病性KCNMA1患者突变如何改变BK通道活性 影响BK电流、动作电位放电以及睡眠和癫痫的昼夜节律 由于它们与各自的LTCC和RyR钙通道相互作用。vbl.使用 以SCN为模型，建议的研究结果将揭示具体的离子 渠道合作伙伴在行动潜力期间协同工作以控制激发，以及如何 以及它们的性质和相互作用的失调如何导致昼夜节律、睡眠、 和癫痫发作障碍。

ABSTRACT Circadian rhythms in physiology are essential for human health, and in mammals, these rhythms are coordinated by a central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN produces the neural code for circadian time through time-of-day dependent modulation of the activity of various ion channels that control action potential firing. The goal of this research is to understand the ion channel properties, interactions, and functional consequences that set these circadian changes in action potential activity in the SCN, focusing on two types of channels that functionally interact during the action potential: BK K+ channels and their Ca2+ channel activators. During the day in SCN, BK channels are activated predominantly by L-type Ca2+ channels (LTCCs), while at night activation depends on Ryanodine Receptors (RyRs). How this switch between the two Ca2+ channel subtypes occurs is not yet known but has important implications during the action potential for any cell where BK channels utilize multiple Ca2+ sources. The proposed studies test the hypothesis that modulation of BK activity via specific Ca2+ channel coupling alters the contribution of BK channels to the action potential. The circadian consequences of this altering this functional coupling will then be probed with Ca2+ channel mutations, as well as BK channel mutations associated with the neurological disorder KCNMA1-linked channelopathy. Our specific aims are to: (1) Determine the key subunits and the physical and functional interactions between BK and Ca2+ channels that regulate firing in day and night in SCN using biochemistry and electrophysiology. The consequences of disrupting these interactions on circadian rhythm will be assessed in the SCN circuit and circadian behavioral outputs, and (2) Determine how pathogenic KCNMA1 patient mutations that alter BK channel activity affect BK current, action potential firing, and the circadian aspects of sleep and seizure as a result of their interactions with the respective LTCC and RyR Ca2+ channels. Using the SCN as a model, the outcome of the proposed studies will reveal how specific ion channel partnerships work together during the action potential to control firing, and how and how dysregulation of their properties and interactions contribute to circadian, sleep, and seizure disorder.