Different relevance of inactivation and F468 residue in the mechanisms of hEag1 
channel blockage by astemizole, imipramine and dofetilide

Gomez-Varela, D.; Contreras-Jurado, C.; Furini, S.; Garcia-Ferreiro, R.; Stuhmer, W.; Pardo, L. A.

doi:10.1016/j.febslet.2006.08.030

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Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide

Gomez-Varela, D., Contreras-Jurado, C., Furini, S., Garcia-Ferreiro, R., Stuhmer, W., & Pardo, L. A. (2006). Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide. FEBS Lett, 580(21), 5059-66. doi:10.1016/j.febslet.2006.08.030.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0009-F221-0 Version Permalink: https://hdl.handle.net/21.11116/0000-0009-F222-F

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https://www.ncbi.nlm.nih.gov/pubmed/16949586 (Any fulltext) Open Access status unknown

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Gomez-Varela, D.¹, Author
Contreras-Jurado, C.¹, Author
Furini, S.¹, Author
Garcia-Ferreiro, R.¹, Author
Stuhmer, W.¹, Author
Pardo, L. A.¹, Author

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1Max Planck Society, ou_persistent13

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Free keywords: Astemizole/chemistry/*pharmacology Benzopyrans/pharmacology Ether-A-Go-Go Potassium Channels/*metabolism Humans Imipramine/*pharmacology Ion Channel Gating/*drug effects Models, Molecular Phenethylamines/*pharmacology Piperidines/pharmacology Point Mutation/*genetics Potassium Channel Blockers/*pharmacology Structure-Activity Relationship Sulfonamides/*pharmacology

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.

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Dates: Published Online: 2006-09-18Date issued: 2006-08-28

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Identifiers: Other: 16949586
DOI: 10.1016/j.febslet.2006.08.030
ISSN: 0014-5793 (Print) 0014-5793 (Linking)

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Title: FEBS Lett

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Pages: - Volume / Issue: 580 (21) Sequence Number: - Start / End Page: 5059 - 66 Identifier: -