PACEMAKER CURRENTS IN THE DEVELOPING MAMMALIAN HEART

本项目的长期目标是了解 心脏组织中的起搏器活动。作为迈向这个女孩的第一步，我们 将调查属性的分布、调节、异质性 和I/F通道的结构。我们最近演示了 非电刺激条件下哺乳动物心室单核细胞I/f电流的存在 生理潜力，以及其他已经证明它存在于 病理状态在正常的舒张期电位范围内。考虑到这些 我们计划使用生物物理技术(渗透性贴片， 全细胞、单通道和剥离贴片记录)来研究 窦房结、心房、浦肯野心内膜、中层心肌I/f的特性 和心外膜。我们将仔细寻找生物物理方面的差异。 监管的性质和机制(其中一些已经 观察)以在每种心脏组织类型中形成I/F分布。这些 研究应有助于开发用于I/F的选择性药理学 在不同的心脏区域。我们还将研究I/F的监管。 更详细地描述窦房结。特别是，我们将扩展我们最近的 演示I/f调节、电压依赖和 丝氨酸-苏氨酸激酶和酪氨酸激酶的电导。我们 将尝试进一步定义这些效应所通过的途径 并且最终结果将尝试进一步定义路径 通过它来施加这些影响，最终的结果是 处理在单通道水平上具有I/F。最后，研究了 任何离子通道都极大地方便了对该通道的了解 结构。我们的最终目标是应用现代技术(聚合酶链式反应、表达和 抑制衣物)在相关尝试中获得I/F的克隆 频道。综上所述，这些研究的分布，调制和 I/F的结构应大大增强我们对这一重要问题的认识 心脏通道，并有望提供新的方法来 心律失常的治疗。

The long term goals of this project are to understand the basis of pacemaker activity in cardiac tissues. As a first step towards this gal we will investigate the distribution, regulation, heterogeneity of properties and structure of the i/f channel. We have recently demonstrated the existence of the i/f current in mammalian ventricular monocytes at non- physiologic potentials, and others have demonstrated its presence in pathologic conditions in the normal diastolic potential range. Given these observations we plan to use biophysical techniques (permeabilized patch, whole cell, single channel and pulled off patch recording) to study the properties of i/f in SA node, atrium, Purkinje endocardium, mid-myocardium and epicardium. We will look carefully for differences in biophysical properties and mechanisms of regulation (some of which have already been observed) to develop a profile of i/f in each cardiac tissue type. These studies should help in the development of a selective pharmacology for i/f in different cardiac regions. We will also study the regulation of i/f in sinus node in more detail. In particular we will expand on our recent observations demonstrating regulation of i/f, voltage dependence and conductance by serine-threonine kinases as well as tyrosine kinases. We will attempt to further define the pathways through which these effects are exerted and the net result will attempt to further define the pathways through which these effects are exerted and the net result these treatments have on i/f at the single channel level. Finally, the study of any ion channel is greatly facilitated by a knowledge of the channel structure. Our last aim is to apply modern techniques (PCR, expression and suppression clothing) in a concerned attempt to obtain a clone of the i/f channel. Taken together these studies of the distribution, modulation and structure of i/f should greatly enhance our knowledge of this important cardiac channel, as well as hopefully provide new approaches to the treatment of disturbances of cardiac rhythm.