The Structural Basis of Antiarrhythmic Drug Binding in Voltage-gated Ion Channels

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Abstract/Project Summary Cardiac arrhythmias affect millions of Americans and are a common cause of morbidity and mortality in older Americans, as well as health care expenditures. They have many causes including inherited gene mutations, electrolyte disturbances, and drug side effects—though all of these causes share the misfiring of voltage-gated ion channels in myocardium. Anti-arrhythmic drugs (AAD) are widely used to treat both atrial and ventricular arrhythmias by blocking such channels, though there is currently a limited understanding of the AAD molecular mechanism of action on a structural level. In this proposal, I aim to study AADs in model voltage-gated sodium and calcium channels, using the widely used sodium channel blocker AAD lidocaine and flecainide as well as the widely used calcium channel blocker AAD diltiazem. I will use established techniques of electrophysiology and X-ray crystallography to study AAD in complex with bacterial voltage-gated sodium and calcium channels, while working to establish new structural models of the AAD binding site using concatenated bacterial channels, higher order channels, and Cryo-EM methods. I expect these experiments to allow for a better understanding of voltage-gated ion channel physiology and aid in the design of safer and more effective AAD, as well as novel therapeutics that may be used for treatment of atrial and ventricular arrhythmias.