NS1643 enhances ionic currents in a G604S‐WT hERG co‐expression system associated with long QT syndrome 2

Summary Loss of function mutations in the human ether‐a‐go‐go‐related gene ( hERG ) cause long QT syndrome type 2 ( LQT 2). Most LQT 2 patients are heterozygous mutation carriers in which the mutant hERG exerts potent dominant‐negative effects. 1, 3‐bis‐(2‐hydroxy‐5‐trifluoromethyl‐phenyl)‐urea ( NS 1643) is known to enhance IK r in WT ‐ hERG . We investigated its actions following lipofectamine‐induced expression of both mutant G604S‐ and WT ‐ hERG in the heterologous HEK 293 expression system. Cells transfected with pc DNA 3‐G604S‐ hERG did not lead to any expression of detectable currents whether before or following NS 1643 challenge. Cells transfected with both pc DNA 3‐ WT ‐ hERG and pc DNA 3‐G604S‐ hERG showed reduced hERG currents compared to those transfected with pc DNA 3‐G604S‐ hERG consistent with the reduced trafficking and formation of modified heteromeric WT ‐G604S channels reported on earlier occasions. Nevertheless, NS 1643 then continued to produce concentration‐ and voltage‐dependent increases in hERG current amplitude. It did not affect the voltage dependence of activation, recovery from inactivation and deactivation. However, NS 1643 (30 μmol/L) slowed steady state inactivation and shifted the steady state half maximal activation voltage ( V 1/2 ) of the inactivation curve by +10 mV , and significantly increased the time constants of inactivation. Our present experimental results suggest that NS 1643 significantly increases ion current and attenuates its inactivation in cells co‐expressing G604S‐ hERG and WT ‐ hERG . These findings raise the possibility that hERG channel activators offer potential treatment strategies for inherited LQT2.