Maprotiline block of the human ether -a -go -go -related gene (HERG) K+ channel

Maprotiline, an atypical antidepressant, can induce prolonged QT andtorsades de pointes. We studied the effects of maprotiline on humanether- a- go- go-related gene(HERG) channels expressed inXenopus oocytes and HEK293 cells. Maprotiline induced a concentration-dependent decrease in current amplitudes at the end of the voltage steps and tail currents of HERG. The V1/2 values in the absence and presence of 1–20 μM maprotiline were not significantly different, while the values decreased according to the concentrations of the drug at 50–300 μM. The IC50 for a maprotiline block of HERG current inXenopus oocytes did not change according to depolarization; 39.5 ± 3.2 (μM at -40 mV and 43.6 ± 2.8 μM at +40 mV. The block of HERG by maprotiline was examined after treatment of trinitrobenzene sulfonic acid (TNBS), an amino-group reagent that neutralizes the positively charged amino-groups of peptide N-terminal and lysine residues. TNBS inhibited the change of V1/2 values induced by 50–300 mM maprotiline, and aggravated the drug-induced gmax decrease. The IC50 for the maprotiline-induced blockade of HERG currents in HEK293 cells at 36°C was 0.13 nM at +20 mV. Our findings suggest that the arrhythmogenic side effects of maprotiline are caused by a blockade of HERG and possibly by a blockade of delayed rectifier K+ channel.