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。作为接近这个女孩的第一步， 将研究这些特性的分布、调节和异质性 以及I/F信道的结构。我们最近展示了 在非缺血条件下，哺乳动物心室单核细胞I/F电流的存在 生理潜力，和其他人已经证明其存在， 正常舒张电位范围内的病理状况。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、单通道和脱落贴片记录）来研究 窦房结、心房、浦肯野内膜、中层心肌的i/f特性 和心外膜。我们将仔细寻找生物物理学上的差异， 管理的性质和机制（其中一些已经被 观察）以在每种心脏组织类型中形成I/F的分布。这些 研究应有助于发展i/f的选择性药理学 在不同的心脏区域。我们亦会研究如何规管 窦房结更详细。特别是，我们将扩大我们最近的 观察表明I/F的调节、电压依赖性和 通过丝氨酸-苏氨酸激酶以及酪氨酸激酶的电导。我们 将试图进一步确定这些影响的途径， 最终的结果将试图进一步定义 这些影响是通过什么来发挥的，最终结果是， 治疗在单通道水平上具有I/F。最后，研究 任何离子通道都可以通过对通道的了解而得到极大的促进 结构我们的最后一个目标是应用现代技术（PCR，表达和 在有关的企图获得一个克隆的I/F 频道综合这些研究的分布，调制和 I/F结构应大大提高我们对这一重要问题的认识， 心脏通道，以及希望提供新的方法， 心律紊乱的治疗。

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.