Transfer of rolf S3-S4 linker to HERG eliminates activation gating but spares inactivation.

Abstract:

:Studies in Shaker, a voltage-dependent potassium channel, suggest a coupling between activation and inactivation. This coupling is controversial in hERG, a fast-inactivating voltage-dependent potassium channel. To address this question, we transferred to hERG the S3-S4 linker of the voltage-independent channel, rolf, to selectively disrupt the activation process. This chimera shows an intact voltage-dependent inactivation process consistent with a weak coupling, if any, between both processes. Kinetic models suggest that the chimera presents only an open and an inactivated states, with identical transition rates as in hERG. The lower sensitivity of the chimera to BeKm-1, a hERG preferential closed-state inhibitor, also suggests that the chimera presents mainly open and inactivated conformations. This chimera allows determining the mechanism of action of hERG blockers, as exemplified by the test on ketoconazole.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Choveau FS,El Harchi A,Rodriguez N,Louérat-Oriou B,Baró I,Demolombe S,Charpentier F,Loussouarn G

doi

10.1016/j.bpj.2009.05.060

subject

Has Abstract

pub_date

2009-09-02 00:00:00

pages

1323-34

issue

5

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(09)01162-X

journal_volume

97

pub_type

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