Cardiac Arrythmia: The CaV1.2 L-type calcium channel is critical for normal cardiac function. These channels are open during the plateau phase of the cardiac action potential, and are thus important determinants of the duration of the action potential. Mutations which reduce the calcium dependent inactivation of these channels cause a substantial prolongation of the action potential duration, corresponding to severe long-QT syndrome in patients. Calmodulinopathies represent one such case, where we have shown that a mutation in calmodulin can cause a loss of calcium dependent inactivation of CaV1.2. Evaluation of the action potential through current clamp recordings of a ventricular myocyte harboring a calmodulinopathy mutation demonstrates marked action potential prolongation, indicative of long-QT syndrome. Alternatively, mutations directly on the CaV1.2 channel cause a disease known as Timothy syndrome or Long-QT type 8. Our lab has demonstrated that these mutations can exert a variety of effects on channel gating, with distinct effects on voltage and calcium dependent inactivation. This deficit in channel inactivation results in long-QT syndrome with episodes of life-threatening cardiac arrhythmia. In order to study the pathogenesis of these mutations, we have generated induced pluripotent stem cell (iPSC) derived cardiomyocytes harboring select Timothy syndrome mutations via CRISPR editing. Optical mapping of the iPSC derived cardiomyocytes reveals a spiral wave pattern in cells harboring the mutation, indicative of a reentrant arrhythmia. Using a combination of patch clamp recordings and imaging, we can probe the pathogenic mechanisms underlying these cardiac phenotypes,  with the goal of providing new insight into the pathogenesis and treatment of calcium channelopathies. Our ongoing research includes the development of a novel treatment for CaV1.2 channelopathies, demonstrating how in-depth biophysics can guide new therapeutic avenues.