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Vol. 60, Issue 6, 1343-1348, December 2001
Rammelkamp Center for Education and Research, MetroHealth Campus,
Case Western Reserve University, School of Medicine, Cleveland, Ohio
(E.F., A.M.B.); and I. Physiologisches Institut, Universitaet
Heidelberg, Heidelberg, Germany (W.J.)
The major subunit of the cardiac delayed rectifier current
IKr is encoded by the human ether a-go-go
related gene (HERG). HERG/IKr channels are
blocked selectively by class III antiarrhythmic methanesulfonanilide
drugs such as dofetilide. The binding site for methanesulfonanilides is
believed to be similar for nonantiarrhythmic drugs such as
antihistamines, antibiotics, and antipsychotics. To gain further
insight into the binding site, we examined the minimal structural
changes necessary to transform low-affinity binding of dofetilide by
the related bovine ether a-go-go channel bEAG to
high-affinity binding of HERG. Previously, it was shown that
high-affinity binding in HERG required intact C-type inactivation; the
bovine ether a-go-go K+ channel (bEAG),
unlike HERG, is noninactivating. Therefore, we introduced C-type
inactivation into noninactivating bEAG using site-directed mutagenesis.
Two point mutations in the pore region, T432S and A443S, were
sufficient to produce C-type inactivation. Low concentrations of
dofetilide produced block of bEAG T432S/A443S; unlike HERG, block was
almost irreversible. Substitution of an additional amino acid in
transmembrane domain S6 made the block reversible. Dofetilide blocked
the triply mutated bEAG T432S/A443S/A453S with an IC50
value of 1.1 µM. The blocking potency was 30-fold greater than bEAG
WT and about one third that of HERG WT. We conclude that high affinity
methanesulfonanilide binding to HERG channels is strongly dependent on
C-type inactivation.
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