Maprotiline block of the human ether-a-go-go-related gene (HERG) K+ channel.
Maprotiline, an atypical antidepressant, can induce prolonged QT and torsades de pointes. We studied the effects of maprotiline on human ether-a-go-go-related gene (HERG) channels expressed in Xenopus 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 microM maprotiline were not significantly different, while the values decreased according to the concentrations of the drug at 50-300 microM. The IC50 for a maprotiline block of HERG current in Xenopus oocytes did not change according to depolarization; 39.5 +/- 3.2 microM at -40 mV and 43.6 +/- 2.8 microM 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 degrees C was 0.13 microM 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.
Jo
Su-Hyun
SH
Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Chuncheon, Korea. shjo@cheju.ac.kr
Hong
Hee-Kyung
HK
Jung
Sung Jun
SJ
Chong
Seon Ha
SH
Yun
Ji-Hyun
JH
Koh
Young-Sang
YS
Choe
Han
H
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008376:Maprotiline / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D014982:Xenopus laevis
D018687:Antidepressive Agents, Second-Generation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D008376:Maprotiline; D014302:Trinitrobenzenesulfonic Acid