Comparison Of Herg And Zerg Potassium Channel Function And Pharmacology

There is significant interest in the utility of hERG channel activator compounds to mitigate loss-of-function. Zebrafish (Daniorerio) hearts have been proposed as a whole organ drug screening model. Here, we have investigated the biophysical and pharmacological properties of the zebrafish ortholog of hERG (zERG) to validate the zebrafish whole heart model for activator compound screening. We expressed zERG channels (zKCNH6a) in Xenopus oocytes and characterized channel gating properties using two-electrode voltage clamp. We show that zKCNH6a channel gating is similar to that of hERG. The voltage-dependence of activation of zKCNH6a channels was −8.8±1.1 mV (n=7) compared with −29.0±2.4 mV (n=6) in hERG channels measured from 2 s depolarizing voltage steps (P<0.05). Deactivation gating was accelerated in zKCNH6a channels: τdeact-110mV was 42.7±5.7 ms (n=7) in zKCNH6a compared with 147.0±11.4 ms (n=5) in hERG (P<0.05). The voltage-dependence of inactivation gating in zKCNH6a channels was −62.0±0.9 mV (n=6) compared with −42.1±1.8 mV (n=6) in hERG (P<0.05). Despite these differences, zKCNH6a channels produced a characteristic resurgent current in response to an action potential voltage waveform that was similar to that observed from hERG channels. zKCNH6a channels displayed a sensitivity to blocker compounds that was similar to hERG channels: dofetilide (5 μM) and terfenadine (5 μM) produced 83±2% (n=5) and 74±2% (n=5) block of zKCNH6a channels, respectively, and 89±4% (n=5) and 82±4% (n=5) block of hERG channels, respectively. Activator compounds NS-1643 (30 μM), PD-118057 (10 μM) and RPR-260243 (10 μM) increased maximal relative conductance 1.5-, 2.4- and 2.3-fold, respectively, in zKCNH6a (n=6), and 1.6-, 1.4- and 2.3-fold in hERG (n=4-6). These data represent, to our knowledge, the first characterization of zKCNH6a channels and suggest that the zebrafish whole heart model may serve as a valuable tool in the screening of hERG-modifying compounds.