Insights into ion channel structure and function in the heart: Impact of computational biology

Heart rate and myocardial contraction are mediated by a complex system of ionic channels and pumps. Significant increases in cardiac action potential duraction can lead to Torsade des Pointes, ventricular fibrillation, and sudden death. Understanding the biophysical mechanisms behind control of action potential duration is necessary for revealing both the cause and treatment of disease. Homology modeling of the C-terminus of SCN5A predicts a structured proximal half. This is confirmed through circular dichroism experiments that provide direct evidence that the proximal half is mostly (∼70%) helical in nature. Patch clamp experiments where the distal unstructured half is truncated show no gating changes, implying that only the structured, proximal half confers the inactivation properties seen in normal and mutant channels. Another type of modeling, electrophysiological cellular modeling of adrenergic control of ventricular cells allows us to investigate the role of microsignaling domains in arrhythmogenesis. We have developed a computational reconstruction of adrenergic control of not only calcium channels and homeostasis, but also of potassium and sodium channels. Our data provide a detailed investigation of rate adaptation in cells with normal and mutant (LQT-1 and LQT5) potassium channels, and demonstrate that the selective disruption of PKA-dependent dating changes in the IKs channel are highly problematic. Additional cellular modeling reveals an intriguing mechanism of arrhythmogenesis for a specific sodium channel mutation, D1790G. Modeling the experimentally observed changes in the mutant channels suggests that the cardiac sodium channel is, in fact, regulated by cAMP. Computational modeling of protein structure and cellular electrophysiology provide us with new insights to the mechanisms of channel gating.