Targeting cardiac potassium channels for state-of-the-art drug discovery

Abstract

Introduction: Cardiac K⁺ channels play a critical role in maintaining the normal electrical activity of the heart by setting the cell resting membrane potential and by determining the shape and duration of the action potential. Drugs that block the rapid (I_Kr) and slow (I_Ks) components of the delayed rectifier K⁺ current have been widely used as class III antiarrhythmic agents. In addition, drugs that selectively target the ultra-rapid delayed rectifier current (I_Kur) and the acetylcholine-gated inward rectifier current (I_KAch) have shown efficacy in the treatment of patients with atrial fibrillation. In order to meet the future demand for new antiarrhythmic agents, novel approaches for cardiac K⁺ channel drug discovery will need to be developed. Further, K⁺ channel screening assays utilizing primary and stem cell-derived cardiomyocytes will be essential for evaluating the cardiotoxicity of potential drug candidates.

Areas covered: In this review, the author provides a brief background on the structure, function and pharmacology of cardiac voltage-gated and inward rectifier K⁺ channels. He then focuses on describing and evaluating current technologies, such as ion flux and membrane potential-sensitive dye assays, used for cardiac K⁺ channel drug discovery.

Expert opinion: Cardiac K⁺ channels will continue to represent significant clinical targets for drug discovery. Although fluorescent high-throughput screening (HTS) assays and automated patch clamp systems will remain the workhorse technologies for identifying lead compounds, innovations in the areas of microfluidics, micropatterning and biosensor fabrication will allow further growth of technologies using primary and stem cell-derived cardiomyocytes.

Keywords:

• antiarrhythmic agents
• cardiac
• potassium channels
• screening
• sensors

Declaration of interest

KB Walsh is funded by a National Institutes of Health Grant (NS071530). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

This box summarizes key points contained in the article.