title: Maprotiline block of the human ether-a-go-go-related gene (HERG) K+ channel.
abstract: 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.
authors.affiliation: Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Chuncheon, Korea. shjo@cheju.ac.kr
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
authors.forename: Hee-Kyung
authors.initials: HK
authors.lastname: Hong
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Jung
authors.forename: Seon Ha
authors.initials: SH
authors.lastname: Chong
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Yun
authors.forename: Young-Sang
authors.initials: YS
authors.lastname: Koh
authors.forename: Han
authors.initials: H
authors.lastname: Choe
mesh_terms: 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
chemical_list: 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