title: Effects of donepezil on hERG potassium channels.
abstract: Donepezil is a potent, selective inhibitor of acetylcholinesterase, which is used for the treatment of Alzheimer's disease. Whole-cell patch-clamp technique and Western blot analyses were used to study the effects of donepezil on the human ether-a-go-go-related gene (hERG) channel. Donepezil inhibited the tail current of the hERG in a concentration-dependent manner with an IC50 of 1.3 μM. The metabolites of donepezil, 6-ODD and 5-ODD, inhibited the hERG currents in a similar concentration-dependent manner; the IC50 values were 1.0 and 1.5 μM, respectively. A fast drug perfusion system demonstrated that donepezil interacted with both the open and inactivated states of the hERG. A fast application of donepezil during the tail currents inhibited the open state of the hERG in a concentration-dependent manner with an IC50 of 2.7 μM. Kinetic analysis of donepezil in an open state of the hERG yielded blocking and unblocking rate constants of 0.54 µM(-1)s(-1) and 1.82 s(-1), respectively. The block of the hERG by donepezil was voltage-dependent with a steep increase across the voltage range of channel activation. Donepezil caused a reduction in the hERG channel protein trafficking to the plasma membrane at low concentration, but decreased the channel protein expression at higher concentrations. These results suggest that donepezil inhibited the hERG at a supratherapeutic concentration, and that it did so by preferentially binding to the activated (open and/or inactivated) states of the channels and by inhibiting the trafficking and expression of the hERG channel protein in the plasma membrane.
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, 222 Banpo-daero, Seocho-gu, Korea.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Chae
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Hong Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: In-Beom
authors.initials: IB
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Ki-Wug
authors.initials: KW
authors.lastname: Sung
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, 222 Banpo-daero, Seocho-gu, Korea. Electronic address: sjhahn@catholic.ac.kr.
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
mesh_terms: D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005473:Fluoxetine; D007189:Indans; D010880:Piperidines; D017367:Selective Serotonin Reuptake Inhibitors; C534900:6-O-desmethyl donepezil; C000606913:KCNH2 protein, human
keywords: Alzheimer׳s disease; Channel trafficking; Donepezil; hERG