© 1997 American Heart Association, Inc.
Articles |
Rapid Inactivation Determines the Rectification and [K+]o Dependence of the Rapid Component of the Delayed Rectifier K+ Current in Cardiac Cells
From the Vanderbilt University School of Medicine, Departments of Medicine and Pharmacology, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 532C Medical Research Building I, Nashville, TN 37232-6602.
Abstract Two characteristic features of the rapid component
of the cardiac delayed rectifier current (IKr)
are prominent inward rectification and an unexpected reduction in
activating current with decreased [K+]o.
Similar features are observed with heterologous expression of
HERG, the gene thought to encode the channel carrying
IKr; moreover, recent studies indicate that the
mechanism underlying rectification of HERG current is the
inactivation that channels rapidly undergo during depolarizing pulses.
The present studies were designed to determine the mechanism of
IKr rectification and
[K+]o sensitivity in the mouse atrial myocyte
cell line, AT-1 cells. Reducing [Mg2+]i to 0,
which reverses inward rectification of some K+ channels,
did not alter IKr current-voltage relationships,
although it did decrease sensitivity to the IKr
blockers dofetilide and quinidine 2- to 5-fold. To determine the
presence and extent of fast inactivation of IKr
in AT-1 cells, a brief hyperpolarizing pulse (20 ms to -120 mV) was
applied during long depolarizations. Immediately after this pulse, a
very large outward current that decayed rapidly to the previous
activating current baseline was observed. This outward current
component was blocked by the IKr-specific
inhibitor dofetilide, indicating that it
represented recovery from fast inactivation during the
hyperpolarizing step, with fast reinactivation during the return to
depolarized potential. With removal of inactivation using this
approach, current-voltage relationships for IKr
([K+]o, 1 to 20 mmol/L) were linear and
reversed close to the predicted Nernst potential for K+. In
addition, decreased [K+]o decreased the time
constants for open
inactivated and
inactivatedopen transitions. Thus, in these cardiac
myocytes, as with heterologously expressed HERG,
IKr undergoes fast inactivation that determines
its characteristic inward rectification. These studies demonstrate that
the mechanism underlying decreased activating current observed at low
[K+]o is more extensive fast inactivation.
Key Words: K+ current • delayed rectifier • extracellular K+ • fast inactivation • heart
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