Analysis of Toxin-Induced Changes in Action Potential Shape for Drug Development

Abstract

The generation of an action potential (AP) is a complex process in excitable cells that involves the temporal opening and closing of several voltage-dependent ion channels within the cell membrane. The shape of an AP can carry information concerning the state of the involved ion channels as well as their relationship to cellular processes. Alteration of these ion channels by the administration of toxins, drugs, and biochemicals can change the AP’s shape in a specific way, which can be characteristic for a given compound. Thus, AP shape analysis could be a valuable tool for toxin classification and the measurement of drug effects based on their mechanism of action. In an effort to begin classifying the effect of toxins on the shape of intracellularly recorded APs, patch-clamp experiments were performed on NG108-15 hybrid cells in the presence of veratridine, tetraethylammonium, and quinine. To analyze the effect, the authors generated a computer model of the AP mechanism to determine to what extent each ion channel was affected during compound administration based on the changes in the model parameters. This work is a first step toward establishing a new assay system for toxin detection and identification by AP shape analysis.