Targeting cardiac potassium channels for state-of-the-art drug discovery.
BACKGROUND
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 (IKr) and slow (IKs) 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 (IKur) and the acetylcholine-gated inward rectifier current (IKAch) 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.


METHODS
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.


CONCLUSIONS
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.
University of South Carolina, School of Medicine, Department of Pharmacology, Physiology and Neuroscience , Columbia, SC 29209 , USA +1 803 216 3519 ; +1 803 216 3538 ; walsh@uscmed.sc.edu.
Kenneth B
KB
Walsh
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels
antiarrhythmic agents; cardiac; potassium channels; screening; sensors