ION CHANNELS, ACTION POTENTIALS, AND QUANTAL SECRETION

大电导钙和电压依赖性钾通道(称为BK 通道)是耦合变化的无处不在的分布离子通道 亚膜上的钙离子对细胞电兴奋性的调节。 BK通道激活与钙离子内流的这种偶联起到了负面作用 动作电位中终止钙内流的反馈作用。这 对于从发射机终端到终端的各种过程都至关重要 突触释放，神经内分泌激素分泌的调节 细胞，以及耳蜗毛细胞的频率调节。这 提案旨在定义基本BK渠道的关键属性 它们的生理作用。此外，该提案将评估 假设BK通道可能在细胞周期调控中起关键作用 电的兴奋性和分泌性，部分原因是选择性 与特定的钙通道亚型相关。要解决这些问题 问题，膜片钳记录方法，共聚焦成像 免疫组织化学定位离子通道和碳纤维电极 大鼠量子分泌信号的(CFE)记录 肾上腺嗜铬细胞将被利用。该提案以一份 BK通道激活如何严重依赖于 选择性偶联到特定的钙离子通道。然后，它前进到 BK通道的生理作用及其意义 BK通道与Ca~(2+)通道的偶联可能具有两者的调节作用 细胞的兴奋性和分泌物。在这里制定的原则 可能不仅对神经内分泌细胞有重要意义，而且 对于BK通道激活依赖于 高浓度的钙离子只存在于开放的钙离子附近 频道。BK通道本地化功能异常将受到影响 对正常的兴奋性细胞功能有显著影响。因此，理解 BK通道在调节递质释放和释放中的作用 在神经元兴奋性的调节中是一个关键因素 能够识别与以下各项相关的关键变更 突触传递、分泌或兴奋性的病理学。

Large conductance Ca2+ -and voltage-dependent K+ channels (termed BK channels) are ubiquitously distributed ion channels that couple changes in submembrane Ca2+ to regulation of cellular electrical excitability. This coupling of BK channel activation to Ca2+ influx plays a negative feedback role to terminate Ca2+ influx during action potentials. This is critical to processes as diverse as the termination of transmitter release at synapses, regulation of hormone secretion from neuroendocrine cells, and the frequency tuning of hair cells in the cochlea. This proposal seeks to define the key properties of BK channels underlying their physiological roles. Furthermore, the proposal will evaluate the hypotheses that the BK channel may play a key role in the regulation of electrical excitability and secretion, in part, because of a selective association with particular subtypes of Ca2+ channels. To address these issues, patch-clamp recording methodologies, confocal imaging of immunohistochemically localized ion channels, and carbon fiber electrode (CFE) recordings of quantal secretory signals from individual rat adrenal chromaffin cells will be utilized. The proposal begins with an examination of how BK channel activation may be critically dependent on selective coupling to particular Ca2+ channels. It then proceeds to the physiological roles played by BK channels and the implications that coupling of BK channels to Ca2+ channels may have both for regulation of cellular excitability and secretion. The principles developed here are likely to be of significance not only for neuroendocrine cells, but for all excitable cells where BK channel activation is dependent on the high concentrations of Ca2+ only found in the vicinity of open Ca2+ channels. Abnormal function on localization of BK channels will impact significantly on normal excitable cell function. Thus, understanding the role of BK channels both in regulation of transmitter release and in regulation of neuronal excitability is a critical element in being able to identify the key alterations that occur in association with pathologies of synaptic transmission, secretion, or excitability.