Abstract
A challenge in ion channel drug discovery is the need to screen a large number of compounds and to measure the pharmacology of drug-ion channel interaction. Automated patch clamp (APC) makes it possible to measure the pharmacology of many compounds; however, the throughput required for high throughput screening of compound libraries has been out of reach of the first generation of APC instruments. Screening of large compound libraries has been done using indirect methodologies with higher false positive and false negative errors. The Qube is a 384 channel, gigaohm-seal based APC instrument for recordings from voltage-gated and ligand-gated ion channels. It offers the capability to screen large compound libraries for ion channel block or modulation. Data are obtained with a throughput of more than 30,000 wells tested per 24 hours. In this study, we did high throughput, voltage clamp recordings of Nav1.7, hERG and ASIC1A on the Qube. Recordings were made on the QChip384 planar patch clamp consumable. Here we demonstrate throughput of up to 1500 wells tested per hour with a 95% success rate using multihole QChips. Using Nav1.7 and hERG expressing cells we demonstrate that the recording are stable and have good voltage control for at least 30 minutes. By repetitive alternating additions of high and low pH on the ASIC1A expressing cells, we demonstrate the advantages of the liquid flow system in the QChip: the QChip384 has flow channels and complete wash in/washout and indefinite waste. The capability of the Qube to handle 384 sites simultaneously combined with the QChip384 architecture enable high throughput screening of compounds with the highest output of true, direct electrophysiological recordings with an uncompromised data quality.
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