Referenced in: none

Automatically associated channels: Kv11.1

Title: Development of a high-throughput electrophysiological assay for the human ether-à-go-go related potassium channel hERG.

Authors: Daniel J Gillie, Steven J Novick, Brian T Donovan, Lisa A Payne, Claire Townsend

Journal, date & volume: J Pharmacol Toxicol Methods, 2013 Jan-Feb , 67, 33-44

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23103595

Abstract
Drug-induced prolongation of the QT interval via block of the hERG potassium channel is a major cause of attrition in drug development. The advent of automated electrophysiology systems has enabled the detection of hERG block earlier in drug discovery. In this study, we have evaluated the suitability of a second generation automated patch clamp instrument, the IonWorks Barracuda, for the characterization of hERG biophysics and pharmacology.All experiments were conducted with cells stably expressing hERG. Recordings were made in perforated patch mode either on a conventional patch clamp setup or on the IonWorks Barracuda. On the latter, all recordings were population recordings in 384-well patch plates.HERG channels activated with a V(1/2)=-3.2±1.6mV (n=178) on the IonWorks Barracuda versus -11.2±6.1mV (n=9) by manual patch clamp. On the IonWorks Barracuda, seal resistances and currents were stable (<30% change) with up to six cumulative drug additions and 1-min incubations per addition. Over 27 experiments, an average of 338 concentration-response curves were obtained per experiment (96% of the 352 test wells on each plate). HERG pharmacology was examined with a set of 353 compounds that included well-characterized hERG blockers. Astemizole, terfenadine and quinidine inhibited hERG currents with IC(50) values of 159nM, 224nM and 2μM, respectively (n=51, 10 and 18). This set of compounds was also tested on the PatchXpress automated electrophysiology system. We determined through statistical methods that the two automated systems provided equivalent results.Evaluating drug effects on hERG channels is best performed by electrophysiological methods. HERG activation and pharmacology on the IonWorks Barracuda automated electrophysiology platform were in good agreement with published electrophysiology results. Therefore, the IonWorks Barracuda provides an efficient way to study hERG biophysics and pharmacology.