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 pc DNA3-G604S- hERG did not lead to any expression of detectable currents whether before or following NS1643 challenge. Cells transfected with both pc DNA3- WT- hERG and pc DNA3-G604S- hERG showed reduced hERG currents compared to those transfected with pc DNA3-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. [ABSTRACT FROM AUTHOR]