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

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Clinical and Experimental Pharmacology and Physiology

Published online on


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.