Functional Role of Potassium Channels in Astrocytes

描述（由申请人提供）：细胞外突触间隙中K+和谷氨酸水平不受调节导致兴奋性毒性和神经元细胞死亡。 星形胶质细胞对这些代谢物的缓冲作用是主要的控制机制，星形胶质细胞中钾电导的改变与许多神经系统疾病相关，包括癫痫和创伤性脑损伤所致的损伤，表明其在调节一般神经元兴奋性和突触传递中的关键作用。 星形胶质细胞膜中的内向整流钾（Kir）通道被认为主要负责维持星形胶质细胞膜电位和钾缓冲/虹吸。 然而，星形胶质细胞Kir电流的分子基础，其整流特性，以及整流在K+缓冲/虹吸中的作用仍不清楚。 我们的目标是评估在正常和病理条件下星形胶质细胞功能的不同钾通道的贡献。 我们的工作假设是，在正常条件下，Kir 4.1在钾缓冲和谷氨酸清除中起着重要作用，而Kir 6.1在缺血期间变得重要。 为了解决这一假设，我们提出了以下具体目标：目标1：检查候选胶质细胞Kir通道的生物物理特性。 目的2：研究不同分子实体在胶质细胞Kir通道活性和K+缓冲中的作用。 目标3：为了检验Kir4.1主要负责谷氨酸诱导的兴奋性毒性期间的神经保护，而Kir6.1在缺血期间起保护神经元的作用的假设。 这些研究的结果将提供深入了解钾通道功能的星形胶质细胞在生理和病理条件下，并可能导致治疗神经系统功能障碍。

DESCRIPTION (provided by applicant): Unregulated levels of K+ and glutamate in the extracellular synaptic space lead to excitotoxicity and neuronal cell death. Buffering of these metabolites by astrocytes is the major controlling mechanism, and alterations in potassium conductance in astrocytes have been associated with many neurological disorders, including epilepsy and impairments due to traumatic brain injury, demonstrating their critical role in modulation of general neuronal excitability and synaptic transmission. Inward rectifying potassium (Kir) channels in astrocyte membranes are believed to be primarily responsible both for maintaining the astrocyte membrane potential and for potassium buffering/siphoning. However, the molecular basis of astrocyte Kir currents, their rectification properties, and the role of rectification in K+ buffering/siphoning remains unclear. Our goal is to assess the contribution of the different potassium channels in astrocyte function during normal and pathological conditions. Our working hypothesis is that Kir 4.1 plays a major role in potassium buffering and glutamate clearance during normal conditions, whereas Kir 6.1 becomes important during ischemia. To address this hypothesis, we propose the following specific aims: Aim 1: To examine the biophysical properties of candidate glial cell Kir channels. Aim 2: To determine the role of different molecular entities in glial cell Kir channel activity and K+ buffering. Aim 3: To test the hypothesis that Kir4.1 is primarily responsible for neuroprotection during glutamate-induced excitotoxicity, whereas Kir6.1 functions to protect neurons during ischemia. The results of these studies will provide insight into potassium channel function in astrocytes under physiological and pathological conditions and may lead to treatments for nervous system dysfunctions.