title: Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide.
abstract: The relevance of a point mutation at the C-terminal end of the S6 helix (F468) and the introduction of C-type inactivation in the blockage of hEag1 channels by astemizole, imipramine and dofetilide was tested. C-type inactivation decreased block by astemizole and dofetilide but not imipramine, suggesting different binding sites in the channel. F468C mutation increased IC(50) for astemizole and imipramine but in contrast to HERG channels, only slightly for dofetilide. Together with measurements on recovery of blocking, our observations indicate that the mechanism of hEag1 blockage by each of these drugs is different, and suggest relevant structural differences between hEag1 and HERG channels.
authors.affiliation: Max-Planck-Institute of Experimental Medicine, Department of Molecular Biology of Neuronal Signals, Hermann-Rein-Str. 3, 37075 Göttingen, Germany. Gomez@em.mpg.de
authors.forename: David
authors.initials: D
authors.lastname: Gómez-Varela
authors.forename: Constanza
authors.initials: C
authors.lastname: Contreras-Jurado
authors.forename: Simone
authors.initials: S
authors.lastname: Furini
authors.forename: Rafael
authors.initials: R
authors.lastname: García-Ferreiro
authors.forename: Walter
authors.initials: W
authors.lastname: Stühmer
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pardo
mesh_terms: D016589:Astemizole / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008958:Models, Molecular; D010627:Phenethylamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D010627:Phenethylamines; D010880:Piperidines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C087257:L 706000; D016589:Astemizole; D007099:Imipramine; C063533:dofetilide