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

Loss of function mutations in the human ether-a-go-go-related gene (hERG) cause long QT syndrome type 2 (LQT2). Most LQT2 patients are heterozygous mutation carriers in which the mutant hERG exerts potent dominant-negative effects. 1, 3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) is known to enhance IKr in WT-hERG. We investigated its actions following lipofectamine-induced expression of both mutant G604S- and WT-hERG in the heterologous HEK293 expression system. Cells transfected with pcDNA3-G604S-hERG did not lead to any expression of detectable currents whether before or following NS1643 challenge. Cells transfected with both pcDNA3-WT-hERG and pcDNA3-G604S-hERG showed reduced hERG currents compared to those transfected with pcDNA3-G604S-hERG consistent with the reduced trafficking and formation of modified heteromeric WT-G604S channels reported on earlier occasions. Nevertheless, NS1643 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, NS1643 (30 μmol/L) slowed steady state inactivation and shifted the steady state half maximal activation voltage (V1/2 ) of the inactivation curve by +10 mV, and significantly increased the time constants of inactivation. Our present experimental results suggest that NS1643 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.