Daily Regulation of Ionic Currents

摘要 生理学中的昼夜节律对人类健康至关重要，而在哺乳动物中，这些 节奏是由位于视交叉上的中央生物钟协调的 下丘脑核（SCN）。SCN产生昼夜节律的神经代码 时间通过依赖于时间的调节各种离子通道的活性， 控制动作电位放电。本研究的目的是了解离子通道 属性，相互作用和功能的后果，设置这些昼夜变化， SCN中的动作电位活动，集中在两种类型的通道， 在动作电位过程中相互作用：BK K+通道及其Ca2+通道激活剂。 在SCN的白天，BK通道主要由L型Ca 2+通道激活 （LTCCs），而在夜间激活依赖于Ryanodine受体（RyRs）。这如何 两种Ca2+通道亚型之间的转换尚不清楚，但具有重要意义。 在动作电位的任何细胞，其中BK通道利用多个 Ca2+来源。拟议的研究测试的假设，BK活动的调制，通过 特异性Ca2+通道偶联改变了BK通道对该作用的贡献 潜力改变这种功能耦合的昼夜节律后果将 可以用Ca2+通道突变以及与以下相关的BK通道突变进行探测： KCNMA1相关的神经系统疾病我们的具体目标是：（1） 确定关键亚基以及BK和 使用生物化学和生物化学方法调节SCN中昼夜放电的Ca2+通道 电生理学破坏这些相互作用对昼夜节律的影响 将在SCN回路和昼夜行为输出中评估节律，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发作的昼夜节律方面 这是由于它们与相应的LTCC和RyR Ca 2+通道相互作用的结果。使用 SCN作为一个模型，拟议的研究结果将揭示如何具体的离子 通道伙伴关系在动作电位过程中共同控制放电，以及如何 以及它们的特性和相互作用的失调如何影响昼夜节律，睡眠， 和癫痫症

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.