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Vol. 57, Issue 2, 367-374, February 2000
Department of Medicine, University of Calgary, Calgary, Alberta,
Canada.
This study reports that the affinity of HERG1 A for dofetilide is
decreased from 0.125 ± 0.003 µM for wild-type (WT) channels to
15 ± 3 µM for F656V, a mutation in the COOH-terminal half of the S6. Similarly, the IC50 for quinidine was
increased from 8 ± 4 µM for WT to 219 ± 65 µM for the
F656V mutation, whereas affinity for external tetraethylammonium was
similar for WT (51 ± 10 mM) and F656V (36 ± 10 mM, NS).
Kinetics of onset of inactivation of F656V was similar to WT but
kinetics of deactivation, activation, and recovery from inactivation
differed from WT. However, mutations in nearby amino acids in the S6
more strikingly altered deactivation, activation, and recovery from
inactivation but had little effect on affinity for dofetilide. To
assess the effects of disruption of inactivation, the S631A mutation
was made. The S631A mutation altered the IC50 for
dofetilide to 20 ± 3 µM, but the IC50 for quinidine
was unchanged at 8 ± 4 µM for WT and 10 ± 1 µM for
S631A. To address whether the F656V mutation alters the
IC50 for dofetilide in a channel that does not inactivate,
the double mutation S631A/F656V was made. The IC50 for
dofetilide of the double mutation was 32 ± 3 µM, which is not
substantially different than that of S631A. These data support the
notion that allosteric changes occurring during the process of
inactivation are necessary for high-affinity dofetilide binding. In
conclusion, the Phe-656 residue of HERG is a molecular
determinant of high-affinity dofetilide binding.
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