Rectification & Block of Ion Channel Currents

描述（由申请人提供）：内向整流K（Kir）通道调节许多组织中的兴奋性，并且几种疾病由Kir通道基因突变引起。 在以前的奖项期间，我们证明了可溶性细胞质因子导致内在整流强内向整流，确定这些因素为多胺，并确认它们作为“长孔塞”，以阻止通道渗透途径。 最近两种不同的K通道孔结构的结晶已经阐明了K通道中的渗透和门控机制。 然而，纠正和门控基尔渠道的结构细节仍然不清楚。 初步的数据使我们具体的假设有关的分子细节的多胺诱导整流和配体门控机制在基尔通道。 这些假设将在三个实验目标中进行严格审查，利用生物化学和生物物理技术的组合，以及分子建模，以获得以前无法获得的内部整流和门控机制的见解。 这项工作将提供的信息，将形成合理的治疗心律失常，癫痫和其他疾病的细胞兴奋性通过调制的Kir通道活动的发展的背景。

DESCRIPTION (provided by applicant): Inward rectifying K (Kir) channels regulate excitability in many tissues, and several diseases result from mutations of Kir channel genes. During previous award periods we demonstrated that soluble cytoplasmic factors cause intrinsic rectification in strong inward rectifiers, identified these factors as polyamines, and confirmed that they act as 'long-pore plugs' to block the channel permeation pathway. Recent crystallization of two different K channel pore structures has illuminated mechanisms of permeation and gating in K channels. However, the structural details of rectification and of gating in Kir channels remain unclear. Preliminary data lead us to specific hypotheses regarding the molecular details of polyamine-induction of rectification and of ligand-gating mechanisms in Kir channels. These hypotheses will be critically examined in three experimental Aims, utilizing a combination of biochemical and biophysical techniques, together with molecular modeling to gain previously unobtainable insight to the mechanisms of inward rectification and gating. The work will provide information that will form the background to the development of rational therapies for cardiac arrhythmias, epilepsy and other disorders of cell excitability through modulation of Kir channel activity.