Gating Mechanisms of Retinal Cyclic Nucleotide-Regulated Ion Channels

超极化激活的环核苷酸门控(HCN)离子通道是第一个 在光感受器中发现，在那里它们塑造光反应。他们展示了几个 使它们专门用于视网膜信号的特性：1)它们是弱K+ 选择性，2)它们被膜超极化激活，而不是去极化 在几乎所有其他电压门控通道中都可以看到，以及3)它们由 环核苷酸与胞内结构域的直接结合。我们的长期目标是 了解这些特性的分子机制，以更好地理解 大脑和心脏经络的生理学和病理生理学。在以前的 资助期我们在实现这一目标方面取得了很大进展。我们有 解决了HCN和相关通道的分子结构，并发明了地面- 突破新的荧光方法，使我们能够记录分子重排 与电生理记录同步的完整通道。在这一资助期， 我们建议应用这些方法来确定分子机制。 超极化激活和环核苷酸调制。这些实验将 从而得出了HCN通道如何调节兴奋性的第一张动态图片 神经元和心肌细胞。

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels were first discovered in photoreceptors where they shape the light response. They exhibit several properties that make them specialized for retinal signaling: 1) they are weakly K+ selective, 2) they are activated by membrane hyperpolarization, instead of depolarization seen in virtually every other voltage-gated channel, and 3) they are regulated by the direct binding of cyclic nucleotides to an intracellular domain. Our long term goal is to understand the molecular mechanisms for these properties to better understand the physiology and pathophysiology of the channels in the brain and heart. In previous funding periods we have made great progress toward achieving this goal. We have solved the molecular structures of HCN and related channels and invented ground- breaking new fluorescence methods that allow us to record molecular rearrangements in intact channels simultaneous with electrophysiological recording. In this funding period, we propose to apply these methods to determine the molecular mechanisms of hyperpolarization activation and cyclic nucleotide modulation. These experiments will lead to the first dynamic picture for how HCN channels regulate the excitability of neurons and cardiomyocytes.