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中起着关键作用 在哺乳动物心脏中的潜在持续时间和传播，这些通道对 维持正常的心律。NAV频道表达和属性的更改在 遗传性和获得性心脏病，这些变化可以有深刻的病理生理 后果，包括增加潜在威胁生命的心律失常的风险。尽管它 似乎被普遍接受的是天然的心肌NAV通道在大分子蛋白中起作用 复合体，包括形成孔的NaV1.5亚单位和多个细胞内和跨膜 辅助亚基在调节NAV通道功能中的生理作用及其机制 这些角色随着心肌疾病的改变而改变，人们对此知之甚少。这项新的合作研究 该计划的重点是定义转录后机制涉及的生理调节和 细胞内NAV通道对心肌NaV1.5编码通道的病理生理调节作用 辅助亚单位。已经开发了一种多方面的实验策略来定义分子和 细胞内成纤维细胞生长因子12B、iFGF12B调控作用的细胞机制 NaV1.5编码的NaV-NAV门控上表达的主要iFGF变异体 通道(目标#1)，并测试在衰竭的人类心脏中上调的iFGF12A具有 对心脏NaV1.5编码通道生物物理和药理学特性的不同影响(AIM #2)。其他实验将检验另一种细胞内辅助亚单位--钙调蛋白， CaM与NaV1.5的C末端靠近iFGF结合部位结合，调节iFGF12B/iFGF12A- NAV1.5编码通道选通的中介效果(目标3)。我们还将创建分子细节NAV 通道门控模型，包括由iFGF12A、iFGF12B和Cam进行的NaV1.5调节，并将使用这些模型 目的：探讨iFGF12介导的天然NAV电流调节对心肌细胞电生理的影响。 这些研究将从根本上为分子和细胞机制提供重要的新见解 IFGF12介导的心肌NaV1.5编码通道和进入生理性通道的调节 IFGF12在心脏兴奋性动态调节中的作用这些洞察力将为探索 IFGFs及其与NaV1.5相互作用作为调节NAV通道的新治疗靶点的潜力 遗传性和获得性心律失常的功能。

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.