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.
Voltage-gated sodium (Nav) channels underlie the generation and propagation of action potentials in the mammalian heart, and changes in Nav channel expression or properties associated with inherited or acquired cardiac diseases have profound physiological consequences, including increased risk of arrhythmias and sudden cardiac death. Although considerable evidence suggests that native myocardial Nav channels function in macromolecular complexes, comprising the pore-forming Nav1.5 subunit and multiple accessory subunits, the physiological roles of Nav channel accessory proteins are poorly understood. Combining electrophysiological, optical and molecular genetic approaches in vivo, in vitro, and in silico, the studies here will delineate the mechanisms involved in post-transcriptional regulation of myocardial Nav channels by accessory proteins.
