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J. Biol. Chem., Vol. 277, Issue 26, 23587-23595, June 28, 2002
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From the The structural determinants for the
voltage-dependent block of ion channels are poorly
understood. Here we investigate the voltage-dependent block
of wild-type and mutant human ether-a-go-go related gene (HERG)
K+ channels by the antimalarial compound chloroquine.
The block of wild-type HERG channels expressed in Xenopus
oocytes was enhanced as the membrane potential was progressively
depolarized. The IC50 was 8.4 ± 0.9 µM
when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also
slowed the apparent rate of HERG deactivation, reflecting the inability
of drug-bound channels to close. Mutation to alanine of aromatic
residues (Tyr-652 or Phe-656) located in the S6 domain of HERG
greatly reduced the potency of channel block by chloroquine
(IC50 > 1 mM at 0 mV). However, mutation of
Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by
progressive membrane depolarization, and complete relief from block was
observed at +40 mV. HERG channel block was voltage-independent when the
hydroxyl group of Tyr-652 was removed by mutating the residue to Phe.
Together these findings indicate a critical role for Tyr-652 in
voltage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to
the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by
cation-
Molecular Determinants of Voltage-dependent Human
Ether-a-Go-Go Related Gene (HERG) K+ Channel Block*
,,
**
Unidad de Investigación
"Carlos Méndez" del Centro Universitario de Investigaciones
Biomédicas de la Universidad de Colima, 23000 Colima,
México, § Molecular Systems, Merck Research
Laboratories, West Point, Pennsylvania 19486 and the Departments of
¶ Medicine and Physiology, and ** Eccles Program
in Human Molecular Biology and Genetics, University of Utah,
Salt Lake City, Utah 84112
and -stacking interactions with Tyr-652 and Phe-656 of
multiple subunits.
*
This work was supported by a Fogarty International Research
Collaboration Grant R03TW001211, NHLBI Grant R01HL55236 from the National Institutes of Health, and CONACyT (Mexico) Grant 34954-M.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Eccles Institute of
Human Genetics, University of Utah, 15 N 2030 E, Rm. 4220, Salt Lake
City, UT 84112. Tel.: 801-585-6336; Fax: 801-5853501; E-mail:
michael.sanguinetti@hmbg.utah.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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