MECHANISMS OF DRUG/ION CHANNEL INTERACTIONS

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Cardiac ion channel proteins are the targets for antiarrhythmic drug action. This Project will integrate functional analysis (voltage clamp of ionic currents) and molecular biological techniques to identify blocking mechanisms and channel protein binding domains for antiarrhythmic agents which block potassium channels. Experiments will utilize both native potassium channels in isolated cardiac cells as well as channels cloned from mammalian (including human) heart. Potassium currents will be measured in isolation and without contamination from other ionic currents in the exogenous expression systems, Xenopus oocytes and mouse fibroblasts, which will be used in this Project. The determinants of the interactions of drugs with open channels, including channel gating, voltage-dependence and ion permeation, and with inactivated channels will be tested experimentally and the results used to refine models of drug inhibition of ion currents. Site-directed channel protein modifications and the expression of heteromeric channels will be used to elucidate the molecular determinants of drug action, including identification of drug binding loci on ion channels. The information gained here will feed back to other Projects in this Program which evaluate drug actions in other systems. This Project will improve our understanding of the mechanisms of antiarrhythmic drug action and may thereby point to strategies which will be useful in the development of newer and safer compounds.