Post-Transcriptional Regulation of Myocardial Sodium Channels

电压门控Na+（Nav）通道在动作电位的产生和控制动作中起关键作用 潜在的持续时间和传播在哺乳动物的心脏，这些渠道是至关重要的 维持正常的心律。导航通道表达和属性的变化在 遗传性和获得性心脏病，这些变化可能具有深刻的病理生理学 后果，包括增加可能危及生命的心律失常的风险。虽然 似乎普遍认为天然心肌Nav通道在大分子蛋白中起作用， 复合物，包含成孔Nav1.5亚基和多个细胞内和跨膜 辅助亚基，辅助亚基在调节Nav通道功能中的生理作用以及如何调节Nav通道功能， 这些作用在心肌疾病中的改变还知之甚少。这项新的合作研究 该计划的重点是定义参与生理调节的转录后机制， 细胞内Nav1.5通道对心肌Nav1.5编码通道的病理生理失调 附属亚基一个多方面的实验策略已经开发出来，以确定分子和 细胞内成纤维细胞生长因子12 B，iFGF 12 B， 在未患病的人心脏中表达的主要iFGF变体，对Nav1.5编码的Nav的门控 通道（目的#1），并测试假设iFGF 12 A，这是上调，在失败的人心脏， 对心脏Nav1.5编码通道的生物物理学和药理学特性的不同影响（目的 #2）。另外的实验将检验另一种细胞内辅助亚基，钙调素， CaM结合到Nav1.5的靠近iFGF结合位点的C末端，调节iFGF 12 B/iFGF 12 A-1。 对Nav1.5编码的通道门控的介导作用（目的#3）。我们还将创建分子详细的导航 通道门控模型，包括iFGF 12 A、iFGF 12 B和CaM对Nav1.5的调节，并将使用这些模型 描述iFGF 12介导的天然Nav电流调节对肌细胞电生理学的影响。 这些研究将为分子和细胞机制提供重要的新见解 潜在的iFGF 12介导的心肌Nav1.5编码通道的调节，并进入生理性 iFGF 12在心脏兴奋性的动态调节中的作用。这些见解将有助于探索 iFGFs和iFGF-Nav 1.5相互作用作为新治疗靶点调节Nav通道的潜力 在遗传性和获得性心律失常中发挥作用。

Voltage-gated Na+ (Nav) channels play key roles in action potential generation and in controlling action potential durations and propagation in the mammalian heart, and these channels are critical for the maintenance of normal cardiac rhythms. Changes in Nav channel expression and properties are prevalent in inherited and acquired cardiac diseases, and these changes can have profound pathophysiological consequences, including increasing the risk of potentially life-threatening cardiac arrhythmias. Although it seems generally accepted that native myocardial Nav channels function in macromolecular protein complexes, comprising the pore-forming Nav1.5 subunit and multiple intracellular and transmembrane accessory subunits, the physiological roles of accessory subunits in regulating Nav channel function and how these roles are altered with myocardial disease are poorly understood. This new collaborative research program is focused on defining the post-transcriptional mechanisms involved in the physiological regulation and pathophysiological dysregulation of myocardial Nav1.5-encoded channels by intracellular Nav channel accessory subunits. A multifaceted experimental strategy has been developed to define the molecular and cellular mechanisms underlying the regulatory effects of intracellular Fibroblast Growth Factor 12B, iFGF12B, the main iFGF variant expressed in non-diseased human heart, on the gating of Nav1.5-encoded Nav channels (aim #1), and test the hypothesis that iFGF12A, which is upregulated in failing human heart, has distinct effects on the biophysical and pharmacological properties of cardiac Nav1.5-encoded channels (aim #2). Additional experiments will test the hypothesis that another intracellular accessory subunit, calmodulin, CaM, which binds to the C terminus of Nav1.5 near the iFGF binding site, modulates iFGF12B/iFGF12A- mediated effects on Nav1.5-encoded channel gating (aim #3). We will also create molecularly-detailed Nav channel gating models that include Nav1.5 regulation by iFGF12A, iFGF12B and CaM and will use these models to delineate the impact of iFGF12-mediated regulation of native Nav currents on myocyte electrophysiology. These studies will provide fundamentally important new insights into the molecular and cellular mechanisms underlying iFGF12-mediated regulation of myocardial Nav1.5-encoded channels and into the physiological roles of iFGF12 in the dynamic regulation of cardiac excitability. These insights will inform efforts to explore the potential of iFGFs and of iFGF-Nav1.5 interactions as new therapeutic targets to modulate Nav channel functioning in inherited and acquired cardiac rhythm disorders.