Daily Regulation of Ionic Currents

点击翻译按钮获取中文摘要

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.