title: Effect of terfenadine and pentamidine on the HERG channel and its intracellular trafficking: combined analysis with automated voltage clamp and confocal microscopy.
abstract: The effects of terfenadine and pentamidine on the human ether-a-go-go related gene (hERG) channel current and its intracellular trafficking were evaluated. Green fluorescent protein (GFP)-linked hERG channels were expressed in HEK293 cells, and the membrane current was measured by an automated whole cell voltage clamp system. To evaluate drug effects on channel trafficking to the cell membrane, the fraction of channel present on the cell membrane was quantified by current measurement after drug washout and confocal microscopy. Terfenadine directly blocked the hERG channel current but had no effect on trafficking of hERG channels to the cell membrane after application in culture medium for 2 d. In contrast, pentamidine had no direct effect on the hERG channel current but reduced trafficking of hERG channels. The two drugs inhibited hERG channel function through different mechanisms: terfenadine through direct channel blockade and pentamidine through inhibition of channel trafficking to the cell membrane. Combined use of automated voltage clamp and confocal microscopic analyses would provide insights into the mechanisms of drug-induced QT-prolongation and arrhythmogenesis.
authors.affiliation: Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Shogo
authors.initials: S
authors.lastname: Hamaguchi
authors.forename: Naoko
authors.initials: N
authors.lastname: Iida-Tanaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Oka
authors.forename: Masato
authors.initials: M
authors.lastname: Nishio
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsuki
authors.forename: Iyuki
authors.initials: I
authors.lastname: Namekata
mesh_terms: D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D010419:Pentamidine / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D016593:Terfenadine / Q000494:pharmacology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D010419:Pentamidine; D016593:Terfenadine