PACEMAKER CURRENTS IN THE DEVELOPING MAMMALIAN HEART

该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 将研究属性的分布、调节、异质性 和 i/f 通道的结构。我们最近展示了 哺乳动物心室单核细胞中 i/f 电流的存在 生理潜力，其他人已经证明了它的存在 病理状况在正常舒张电位范围内。鉴于这些 观察我们计划使用生物物理技术（透化贴片， 全细胞、单通道和拉断贴片记录）来研究 SA 结、心房、浦肯野心内膜、心肌中层 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（其中一些已经被 观察）以开发每种心脏组织类型的 i/f 概况。这些 研究应有助于开发 i/f 的选择性药理学 位于不同的心脏区域。我们还将研究 i/f 的调节 窦房结更详细。特别是，我们将扩展我们最近的 观察结果表明 i/f 的调节、电压依赖性和 丝氨酸-苏氨酸激酶以及酪氨酸激酶的电导。我们 将尝试进一步定义这些影响的途径 被发挥，最终结果将尝试进一步定义路径 这些影响是通过它发挥出来的，最终的结果是 处理在单通道级别的 i/f 上进行。最后，研究 对通道的了解极大地促进了任何离子通道 结构。我们的最终目标是应用现代技术（PCR、表达和 压制服装），试图获得 i/f 的克隆 频道。综合这些分布、调制和 i/f 的结构应该大大增强我们对这一重要的知识 心脏通道，并希望提供新的方法 治疗心律紊乱。

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.