Functional interaction between cardiac Na channels and KATP channels

心脏 Na 通道和 KATP 通道之间的功能相互作用

基本信息

批准号：
10160950
负责人：
William A Coetzee
金额：
$ 68.26万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160950
关键词：
ANK3 gene Action Potentials Adherens Junction Animal Model Ankyrins Area Binding Binding Sites Biochemistry Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiovascular system Caveolae Cell Adhesion Cell Communication Cells Characteristics Code Complex Couples Coupling Data Disease Event Fluorescence Microscopy Genes Heart Heart Rate Hybrids Inherited Intercalated disc Investigation Ion Channel Knowledge Lateral Mediating Membrane Microscopy Modeling Molecular Molecular Biology Muscle Cells Na(+)-K(+)-Exchanging ATPase Peptides Physiological Proteins Research Personnel Resolution Role Ryanodine Receptors Shapes Site Small Interfering RNA Stress Surface System Techniques Testing Time Ventricular density design genetic variant imaging modality innovation insight ischemic injury medical schools nanometer patch clamp response scanning ion conductance microscopy syntrophin voltage

项目摘要

SUMMARY Cardiac Na+ channels and KATP channels are generally thought to have very different roles in cardiac electrophysiology. They do, however, share certain characteristics such as being expressed at higher levels at the intercalated disk compared to the lateral membranes and they coexist with desmosomal proteins. Our new data demonstrate that cardiac KATP channels interact with Na+ channels (and with the Na+/K+ ATPase). This proposal will utilize innovate super-resolution microscopy techniques and patch clamping to examine the interaction between Na+ channels and KATP channels. We will identify the membrane subdomains where interaction occurs, the molecular mechanisms responsible for interaction and the functional consequences of interactions. The overall hypotheses is that interaction is particularly prominent at membrane domains at the ICD, that interaction is mediated by specific binding sites in ankyrin-G, and that interaction leads to functional coupling between Na+ channels and KATP channels (via the Na+/K+ ATPase). In a first Aim, we will localize Na+ channels and KATP channels with nanometer precision to membrane subdomains in the lateral membrane (e.g. t-tubules, caveolae, etc.) as well as membrane subdomains at the intercalated disk (e.g. hybrid adhering junctions). A role for ankyrins in targeting channels to these domains will be investigated with siRNA approaches. In a second Aim, we will investigate the molecular mechanisms involved in interaction, testing the hypothesis that Na+ channels and KATP channels bind to similar sites on ankyrins. We will also test the functional consequences of interaction of Na+ channels and KATP channels. These studies will significantly move forward our understanding of Na+ channel and KATP channel and function in the cardiovascular system, and more generally, advance our knowledge on how channel systems in ventricular myocytes physically and functionally interact.

概括心脏NA+通道和KATP通道通常被认为在心脏中具有截然不同的角色电生理学。但是，他们确实具有某些特征，例如在与侧膜相比，插入的磁盘与脱骨蛋白共存。我们的新数据表明心脏KATP通道与Na+通道（以及Na+/K+ ATPase）相互作用。这提案将利用创新的超分辨率显微镜技术和贴片夹具来检查 Na+通道和KATP通道之间的相互作用。我们将确定膜子域相互作用发生，负责相互作用的分子机制和功能后果互动。总体假设是，相互作用在膜域特别突出 ICD，这种相互作用是由安氨酸中特定结合位点介导的，该相互作用导致功能性 Na+通道和KATP通道之间的耦合（通过Na+/K+ ATPase）。在第一个目标中，我们将本地化Na+ 通道和KATP通道具有纳米精度，可与外侧膜中的膜亚域（例如， T型管，小窝等）以及插入式磁盘处的膜子域（例如，混合粘附连接）。 Ankyrins在针对这些域的靶向通道中的作用将使用siRNA研究方法。在第二个目标中，我们将研究与相互作用相互作用的分子机制，测试假设Na+通道和KATP通道与伸肌上的相似位点结合。我们还将测试 Na+通道和KATP通道相互作用的功能后果。这些研究将大大继续我们对Na+通道和KATP通道的理解以及心血管系统中的功能，更一般地，促进我们对频道系统在身体和身体上如何进行身体和在功能上相互作用。