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LQT2
Amplitude Reduction and Loss of Selectivity in the Tail That Wags
the HERG Channel
Gail A. Robertson
W
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position adjacent to three residues thought to single-handedly
ensure high rates of K⫹ conduction through the pore while
excluding Na⫹ entry.19 Whereas most K⫹ channels exhibit the
signature gly-tyr-gly (GYG),20 HERG and other Eag-related
channels have GFG at the corresponding site,3 with a phenylalanine substituting for tyrosine. Mutations at the adjacent
residue in Shaker channels (GYGD) are not well tolerated,20
but when engineered into heteromeric dimers, they reduce the
degree of selectivity for K⫹ over Na⫹ and alter the rate of
C-type inactivation.21 As Duff and colleagues1 show, a
disease mutation at the corresponding site in HERG (GFGN
to D) eliminates selectivity of K⫹ over Na⫹ and disrupts
C-type inactivation as well, underscoring the influence of
residues at this site in the closely related processes of
selectivity and C-type inactivation.22,23
It may seem surprising that a mutation that removes
inactivation, which would increase the relative amplitude of
HERG currents during the peak and plateau phases of the
action potential, could prolong the QT interval. However, in
the absence of an inactivated state from which to recover, the
resurgent current is eliminated and thus cannot contribute to
terminal repolarization.8 –10 What is left is a small, rapid tail
current unable to exert much of a physiological effect. If that
were not enough, the authors observe, the tail currents of the
selectivity-impaired N629D mutant are inward and may be
surprisingly effective at further delaying repolarization and
contributing to arrhythmogenesis. That even a small inward
current could be proarrhythmic is supported by the modeling
study of Clancy and Rudy,24 who show that the persistent
inward current through mutant Na⫹ channels associated with
LQT325 is capable of prolonging the QT interval, even though
it is a mere 2% of its normal peak amplitude. Whether the
inward Na⫹ current tail in the HERG mutant N629D prolongs
the QT interval over and above the simple loss of the
resurgent current could be put to the test using the same
model.
As fascinating as the biophysical defects in channel properties are, one must ask whether long QT in families carrying
the N629D mutation might actually be due to a HERG protein
trafficking defect. The data indicate that the mutant N629D
RNA does not express as well as wild type in oocytes, with
one example showing mutant current amplitudes less than
10% of those of wild type, despite the injection of twice as
much RNA. It would not be the first case in which biophysical defects in channel properties were of secondary importance to failed transport of channels to the plasma membrane
in accounting for the disease process.17 Furthermore, trafficking defects can be exacerbated at physiological temperatures,26,27 potentially limiting the inferences about disease
ithout the ion selectivity of voltage-gated ion
channels, excitable cells could not generate more
than a few millivolts of resting potential, much
less produce action potentials. Even when the loss of selectivity occurs in just one type of K⫹ channel in the heart, the
outcome may be catastrophic, suggests a report in this issue
of Circulation Research.1 A defect in K⫹ selectivity caused
by a mutation near the “signature sequence” in the pore of
HERG channel subunits may contribute as a new mechanism
to the prolongation of the action potential and the associated
susceptibility to life-threatening torsades de pointes
arrhythmias.
Since chromosome 7-linked long-QT syndrome (LQT2)
was first mapped to HERG,2 a relative of the Drosophila and
mammalian eag genes,3 we have learned much about the
pathology of the disease and the underlying physiological
mechanisms that have gone awry. In heterologous expression
systems, the subunits encoded by the wild-type HERG gene
assemble to form channels with the functional properties of
IKr,4,5 an unusual repolarizing current first identified by its
sensitivity to the antiarrhythmic agent E-4031.6 Our understanding of how IKr participates in repolarization has emerged
largely from voltage-clamp analyses of the remarkable tail
currents dominating the HERG current profile. At the positive
voltages typically reached at the peak or plateau of the
ventricular action potential, much of the current is suppressed
by a rapid inactivation mechanism.4,5,7–10 As repolarization
ensues, HERG channels recover from inactivation and linger
in a highly stable open state before closing.11 The result is a
“resurgent current,” a term coined for Na⫹ current in cerebellar Purkinje neurons arising from an analogous gating
process.12 HERG mutations causing long-QT syndrome generally reduce the magnitude of this resurgent current by
altering channel properties13–15 or as a consequence of trafficking defects.16,17
Add to the mounting list of familial HERG mutations
N629D,18 situated conspicuously in a guilty-by-association
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Department of Physiology and Cardiovascular Research
Center, University of Wisconsin – Madison Medical School, Madison,
Wis.
Correspondence to Gail Robertson, Department of Physiology, University of Wisconsin – Madison Medical School, 1300 University Ave,
Madison, WI 53706. E-mail [email protected]
(Circ Res. 2000;86:492-493.)
© 2000 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
492
Robertson
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mechanisms that can be drawn from experiments conducted
in Xenopus oocytes at room temperature. Given the growing
importance of trafficking defects in LQT2, the burden of
proof is on the investigator to eliminate this possibility before
the disease process can be attributed solely to a defect in
channel properties, however compelling the biophysical phenotype may be.
An interesting and paradoxical result of the present study is
that an aspartate adjacent to the signature sequence can
sabotage selectivity in HERG channels whereas it may serve
as part of the normal selectivity filter in Shaker.21 However,
no such K⫹ binding site can be inferred from the superimposed electron density and rubidium difference maps reported
for the KcsA bacterial channel structure, which bears the
GYGD sequence.19 More information should come to light in
the next generation of K⫹ channel structures, which, with
luck, will include a view of HERG at atomic resolution.
Whether its curious GFGN signature translates into threedimensional differences compared with its K⫹ channel brethren remains to be seen.
This study by Duff and colleagues1 is emblematic of the
explosive synergy of basic and clinical research over little
more than a single decade, punctuated in this case by such
milestones as the cloning of the Shaker28 and eag29 channel
genes from Drosophila, the mapping of disease loci on the
human chromosome,2 the structural resolution of a K⫹ channel pore,19 and innumerable structure-function studies along
the way. No less significant are the emerging models30 that
will soon encompass every element of excitability in different
regions of the heart, revealing the mechanistic underpinnings
of the long-QT syndromes at the molecular, cellular, and
systems levels.
References
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KEY WORDS: LQT2
䡲
HERG
䡲
selectivity
䡲
K⫹ channels
LQT2: Amplitude Reduction and Loss of Selectivity in the Tail That Wags the HERG
Channel
Gail A. Robertson
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Circ Res. 2000;86:492-493
doi: 10.1161/01.RES.86.5.492
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