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Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide
Author(s) -
Gómez-Varela David,
Contreras-Jurado Constanza,
Furini Simone,
García-Ferreiro Rafael,
Stühmer Walter,
Pardo Luis A.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.08.030
Subject(s) - astemizole , dofetilide , herg , chemistry , pharmacology , imipramine , medicine , potassium channel , alternative medicine , qt interval , pathology
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.