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Vol. 63, Issue 5, 1051-1058, May 2003
Unidad de Investigación "Carlos Méndez" del Centro
Universitario de Investigaciones Biomédicas de la Universidad de
Colima, Colima, México (J.A.S.-C., T.F., R.A.N.-P.); and
Department of Physiology and Eccles Program in Human Molecular Biology
and Genetics, University of Utah, Salt Lake City, Utah (M.C.S.)
Many common medications block delayed rectifier K+ channels
and prolong the duration of cardiac action potentials. Here we investigate the molecular mechanisms of voltage-dependent block of
human ether-a-go-go-related gene (HERG) delayed
rectifier K+ channels expressed in Xenopus
laevis oocytes by quinidine, an antiarrhythmic drug, and
vesnarinone, a cardiotonic drug. The IC50 values determined
with voltage-clamp pulses to 0 mV were 4.6 µM and 57 µM for
quinidine and quinine, respectively. Block of HERG by quinidine (and
its isomer quinine) was enhanced by progressive membrane depolarization
and accompanied by a negative shift in the voltage dependence of
channel activation. As reported previously for other HERG blockers
(e.g., MK-499, cisapride, terfenadine, chloroquine), the potency of
quinidine was reduced >100-fold by the mutation of key aromatic
residues (Y652, F656) located in the S6 domain. Mutations of Y652
eliminated (Y652F) or reversed (Y652A) the voltage dependence of HERG
channel block by quinidine and quinine. These quinolines contain a
charged N atom that might bond with Y652 by a cation-
interaction.
However, similar changes in the voltage-dependent profile for block of
Y652F or Y652A HERG channels were observed with vesnarinone, a
cardiotonic drug that is uncharged at physiological pH. Together, these
results suggest that voltage-dependent block of HERG results from
gating-dependent changes in the orientation of Y652, a critical
component of the drug binding site, and not from a transmembrane field
effect on a charged drug molecule.
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