PHYSIOLOGY OF CARDIAC ION CHANNELS

这个项目的主要目的是描述分子事件 参与离子渗透和阻断、通道门控和离子通道 调控 特别是，我们的目标是了解 和内向整流通道K1功能的物理基础， 心脏细胞中的起搏通道If。 通道电流将是 使用贴片在离体豚鼠心室和结细胞中研究 钳位技术 将进行通道渗透和阻塞研究 对于内向整流器通道， 整流，特别是细胞内Mg 2+的阻断作用。 的 将检查渗透离子和不渗透离子之间的相互作用， 建模以了解渗透机制， 整流和离子传导路径的结构。 信道 将调查门控，以确定其在纠正中的作用。 为 起搏器通道，离子渗透将研究单价 和二价阳离子，并用渗透能量曲线建模， 确定该通道的非常低的单通道电导的基础 但对Na+和K+的选择性较低。 起搏器门控 通道将被研究，以了解所涉及的动力学状态 在通过超极化电压缓慢激活电流中 起搏器的活动 对于这两种通道，细胞的机制 调制将进行生理检查，我们将尝试 分离和表征的生化途径参与 渠道监管 这些研究结果将提供新的 关于参与的详细分子机制的信息， 内向整流和起搏通道的功能，这将有助于 了解基本的心脏功能，电流的调节， 心脏，Mg2+在心脏中的作用，以及 离子渗透、门控和一般膜通道的调节。 预计这些研究将与人类的生理学有关。 心脏，以及神经，肌肉和其他可兴奋的生理学 细胞

The broad aim of this project is to characterize the molecular events involved in ion permeation and block, channel gating and ion channel regulation. In particular, the goal is an understanding of the molecular and physical basis of the function of the inward rectifier channel K1 and the pacemaker channel If in cardiac cells. The channel currents will be studied in isolated guinea pig ventricular and nodal cells using patch clamp techniques. Channel permeation and block studies will be conducted for the inward rectifier channel to characterize the mechanism of rectification, particularly the effect of block by intracellular Mg2+. The interactions between permeant and impermeant ions will be examined and modeled to gain an understanding of the mechanisms of permeation and rectification, and the structure of the ion conductance pathway. Channel gating will be investigated to ascertain its role in rectification. For the pacemaker channel, ion permeation will be investigated for monovalent and divalent cations and modeled with a permeation energy profile to determine the basis of this channel's very low single-channel conductance but its low selectivity between Na+ and K+. Gating of the pacemaker channel will be studied to learn about the kinetic states that are involved in the slow activation of the current by hyperpolarizing voltage important for the pacemaker activity. For both channels, the mechanisms of cellular modulation will be examined physiologically and we will attempt the isolation and characterization of the biochemical pathways involved in channel regulation. The results of these studies will provide new information about the detailed molecular mechanisms involved in the function of the inward rectifier and pacemaker channels that will help in the understanding of basic cardiac function, regulation of the current in the heart, the role of Mg2+ in the heart, and the molecular mechanisms of ion permeation, gating and regulation of membrane channels in general. These studies are expected to have relevance to the physiology of the heart, as well as the physiology of nerve, muscle, and other excitable cells.