Investigating the Utility of Adult Zebrafish Ex Vivo Whole Hearts to Pharmacologically Screen hERG Channel Activator Compounds

There is significant interest in the potential utility of small molecule activator compounds to mitigate cardiac arrhythmia caused by loss-of-function of hERG1a voltage-gated potassium channels. Zebrafish (Danio rerio) have been proposed as a cost effective, high throughput drug-screening model to identify compounds that cause hERG1a dysfunction. However, there are no reports on the effects of hERG1a activator compounds in zebrafish, and consequently on the utility of the model to screen for potential gain-of-function therapeutics. Here, we examined the effects of hERG1a blocker, and type 1 and type 2 activator, compounds on isolated zkcnh6a (zERG3) channels in the Xenopus laevis oocyte heterologous expression system, as well as action potentials recorded from ex vivo adult zebrafish whole hearts using optical mapping. Our functional data from isolated zkcnh6a channels show that these channels respond to hERG1a channel blockers (dofetilide and terfenadine), and type 1 (RPR260243) and type 2 (NS1643, PD-118057) hERG1a activator compounds, in a similar manner to hKCNH2a channels, with minor differences largely accounted for by subtly different biophysical properties in the two channels. In ex vivo zebrafish whole hearts, two of the three hERG1a activators examined caused abbreviation of the APD, while hERG1a blockers caused APD prolongation. These data represent, to our knowledge, the first pharmacological characterization of isolated zkcnh6a channels and the first assessment of hERG enhancing therapeutics in zebrafish. Our findings suggest that the zebrafish ex vivo whole heart model serves as a valuable tool in the screening of hKCNH2a blocker and activator compounds.