The hERG K+ channel S4 domain L532P mutation: Characterization at 37 °C

hERG (human Ether-a-go-go Related Gene) is responsible for ion channels mediating rapid delayed rectifier potassium current, I-Kr, which is key to cardiac action potential repolarization. Gain-of-function hERG mutations give rise to the SQT1 variant of the Short QT Syndrome (SQTS). Reggae mutant zebrafish, with a S4 zERG mutation (Leucine499Proline; L499P), display arrhythmic features analogous to those seen in the SQTS. The affected S4 domain ERG residue is highly conserved. This study was executed to determine how the homologous hERG mutation (L532P) influences channel function at 37 degrees C. Whole-cell measurements of current (I-hERG) were made from HEK 293 cells expressing WT or L532P hERG. The half maximal activation voltage (V-0.5) of L532P I-hERG was positively shifted by similar to+36 mV compared to WT I-hERG; however at negative voltages a pronounced L532P I-hERG was observed. Both activation and deactivation time-courses were accelerated for L532P I-hERG. The inactivation V-0.5 for L532P I-hERG was shifted by similar to+32 mV. Under action potential (AP) voltage-clamp, L532P I-hERG exhibited a dome-shaped current peaking at similar to+16 mV, compared to similar to-31 mV for WT-I-hERG. The L532P mutation produced an similar to 5-fold increase in the IC50 for dronedarone inhibition of I-hERG. Homology modeling indicated that the 1332 residue within the S4 helix lies closely apposed to the S5 region of an adjacent hERG subunit. Alterations to the S4 domain structure and, potentially, to interactions between adjacent hERG subunits are likely to account for the functional effects of this mutation. (C) 2011 Elsevier B.V. All rights reserved.