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: Su-Hyun Jo, Hee-Kyung Hong, Sung Jun Jung, Seon Ha Chong, Ji-Hyun Yun, Young-Sang Koh, Han Choe
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 30 Issue 4 Pg. 453-60 (Apr 2007) ISSN: 0253-6269 [Print] Korea (South)
• PMID: 17489361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidepressive Agents, Second-Generation
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• Potassium Channel Blockers
• Maprotiline
• Trinitrobenzenesulfonic Acid

Topics

• Animals
• Antidepressive Agents, Second-Generation (pharmacology)
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Female
• Humans
• Maprotiline (pharmacology)
• Potassium Channel Blockers (pharmacology)
• Trinitrobenzenesulfonic Acid (pharmacology)
• Xenopus laevis