PHYSIOLOGY OF CARDIAC ION CHANNELS

这个项目的主要目标是描述分子事件的特征。 涉及离子渗透和阻断、通道门控和离子通道 监管。特别是，我们的目标是了解分子 和内向整流通道K1的功能的物理基础以及 心脏细胞中的起搏通道IF。通道电流将是 斑贴技术在豚鼠离体室结细胞研究中的应用 钳夹技术。将进行河道渗透和堵塞研究 对于内向整流通道，用来表征 整流，尤其是细胞内镁离子的阻断效应。这个 我们将研究预指离子和非指离子之间的相互作用 建模以了解渗透机制和 整流，以及离子电导通路的结构。渠道 将对闸门进行调查，以确定其在整改中的作用。为 起搏器通道，离子渗透性将被研究为单价 和二价阳离子，并用渗透能量分布模拟 确定此通道非常低的单通道电导的基础 但其对Na+和K+的选择性较低。起搏器的门控 将对通道进行研究，以了解所涉及的动力学状态 在电流的缓慢激活中，超极化电压很重要 心脏起搏器的活动。对于这两个通道，细胞的机制 我们将对调制进行生理学检查，我们将尝试 参与的生化途径的分离和鉴定 航道整治。这些研究的结果将提供新的 关于参与的详细分子机制的信息 内向整流器和起搏器通道的功能将有助于 对心脏基本功能的认识，对电流的调节 心脏，镁离子在心脏中的作用，以及镁离子的分子机制 一般情况下，膜通道的离子渗透、门控和调节。 这些研究有望与老年人的生理学相关。 心脏，以及神经、肌肉等易兴奋的生理学 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.