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

• 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
• 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

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.

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