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Updated: Jul 5, 2026
High-throughput Screening for Small-molecule Modulators of Inward Rectifier Potassium Channels
Published on: January 27, 2013
Improved throughput of PatchXpress hERG assay using intracellular potassium fluoride
Haoyu Zeng1, Jacob R Penniman, Fumi Kinose
1Merck Research Laboratories, West Point, PA 19486, USA. haoyu_zeng@merck.com
Insights
Optimizing the human ether-a-go-go-related gene (hERG) channel screening with potassium fluoride improves success rates and data quality. This advancement enhances high-throughput drug discovery, reducing late-stage failures.
Area of Science:
- Cardiovascular pharmacology
- Drug safety assessment
- Ion channel electrophysiology
Background:
- Blockade of the human ether-a-go-go-related gene (hERG) potassium channel can lead to QT prolongation and torsade de pointes, causing drug withdrawals.
- Regulatory agencies mandate in vitro hERG screening for drug candidates.
- Automated patch clamp systems offer higher throughput for early-stage hERG screening compared to manual methods.
Purpose of the Study:
- To optimize an automated patch clamp method for hERG screening using potassium fluoride (KF).
- To evaluate the impact of KF on hERG current properties and screening efficiency.
- To improve the throughput and success rate of hERG screening in drug discovery.
Main Methods:
- Optimization of the PatchXpress 7000A automated patch clamp system.
- Utilized potassium fluoride (KF) in the internal recording solution for hERG current measurements.
- Compared biophysical and pharmacological properties of hERG currents recorded with KF versus standard potassium chloride solutions.
Main Results:
- hERG currents recorded with KF exhibited similar biophysical and pharmacological properties to those recorded with standard potassium chloride solutions.
- The use of KF significantly improved the success rate of hERG screening on the PatchXpress system.
- KF utilization led to a significant increase in the throughput of hERG screening without compromising data quality.
Conclusions:
- Optimized automated patch clamp hERG screening using KF enhances efficiency and reliability.
- This method minimizes the risk of late-stage drug development failures due to hERG channel interactions.
- The KF-based approach is valuable for high-throughput functional hERG screening in pharmaceutical research.
Abstract:
Blockade of the human ether-a-go-go-related gene (hERG) potassium channel, with a consequent possibility of QT prolongation and increased susceptibility to a characteristic polymorphic ventricular arrhythmia, torsade de pointes, is an important cause of withdrawal of drugs from the market. In the aftermath of recent drug withdrawals, regulatory agencies now require in vitro hERG screening of all pharmaceutical compounds that are targeted for human use. To minimize the potential for failure in later-stage drug development, many pharmaceutical and biotechnology companies have begun to use automated patch clamp systems with higher throughput than conventional manual patch-clamp techniques to conduct routine functional hERG screening during drug discovery and early development. We have optimized an automated patch-clamp hERG screening method for the PatchXpress 7000A system (Molecular Devices, Sunnyvale, CA) using potassium fluoride (KF) in the internal recording solution. In this study we show that (1) the biophysical and pharmacological properties of hERG current recorded with KF are similar to those with standard potassium chloride solutions, (2) use of KF significantly improves the success rate of hERG screening using PatchXpress without compromising data quality, and (3) utilization of KF can significantly increase the throughput of hERG screening with PatchXpress.
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