© 2000 American Heart Association, Inc.
Molecular Medicine |
Novel Gain-of-Function Mechanism in K+ Channel–Related Long-QT Syndrome:
Altered Gating and Selectivity in the HERG1 N629D Mutant
From the Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Correspondence to H.J. Duff, Department of Medicine, University of Calgary, 3330 Hospital Dr, NW, Calgary, Alberta, Canada, T2N 4N1. E-mail hduff{at}ucalgary.ca
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Abstract |
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Abstract—The N629D mutation, adjacent to the GFG signature sequence of the HERG1 A K+ channel, causes long-QT syndrome (LQTS). Expression of N629D in Xenopus oocytes produces a rapidly activating, noninactivating current. N629D is nonselective among monovalent cations; permeation of K+ was similar to that of Na+ or Cs+. During repolarization to potentials between -30 and -70 mV, N629D manifested an inward tail current, which was abolished by replacement of extracellular Na+ (Na+e) with extracellular N-methyl-D-glucamine (NMGe). Because LQTS occurs in heterozygous patients, we coexpressed N629D and wild type (WT) at equimolar concentrations. Heteromultimer formation was demonstrated by analyzing the response to 0 [K+]e. The outward time-dependent current was nearly eliminated for WT at 0 [K+]e, whereas no reduction was observed for homomultimeric N629D or for the equimolar coexpressed current. To assess physiological significance, dofetilide-sensitive currents were recorded during application of simulated action potential clamps. During phase 3 repolarization, WT manifested outward currents, whereas homomultimeric N629D manifested inward depolarizing currents. During coexpression studies, variable phenotypes were observed ranging from a reduction in outward repolarizing current to net inward depolarizing current during phase 3. In summary, N629D replaces the WT outward repolarizing tail current with an inward depolarizing sodium current, which is expected to delay later stages of repolarization and contribute to arrhythmogenesis. Thus, the consequences of N629D resemble the pathophysiology seen in LQT3 Na+ channel mutations and may be considered the first LQTS K+ channel mutation that exhibits gain of function.
Key Words: long-QT syndrome • HERG1 • K+ channel • gain of function
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Familial long-QT syndrome (LQTS) results from defects in sodium and potassium ion channels that cause prolongation of cardiac repolarization and arrhythmias.1 LQT2 is associated with mutations of the human ether-a-go-go–related gene, HERG1.2 3 4 5 6 7 8 9 10 The HERG1 primary transcript is alternatively processed, giving rise to at least 3 functional mRNAs, HERG1 A, HERG1 A', and HERG1 B, encoding proteins with distinct physiological properties.11 12 There are several mechanisms by which individual mutations in HERG1 produce LQTS.5 6 7 8 9 Some exert a dominant phenotype through loss of repolarizing current. These include mutations that either cause defects in intracellular transport or result in channels that do not open. Alternatively, V630L forms heterotetramers with wild type (WT) that have reduced open probability due to a negative shift in voltage dependence of inactivation. Abnormally fast deactivation mutations caused by mutations in the N terminus of HERG1 A result in reduction of outward current during phase 3 repolarization and thus LQTS.10 The recently described N629D mutation9 is of particular interest, as it alters the pore selectivity signature sequence from GFGN to GFGD.13 In most K+ channels, including the extensively studied Shaker channel, the signature sequence is GYGD. In Shaker, mutation of GYGD to GYGN results in a nonconducting channel that retains its gating properties.14 Inclusion in the tetramer of 1 or 2 monomers containing D/T, D/N, or D/C mutations yields a conducting channel.15 16 17 Mutation of 2 monomers to D378T in Kv2.1 resulted in a channel with reduced selectivity for K+ over Na+ and strong outward rectification.16 Mutation of Shaker D447 to E in all 4 positions or N in 2 positions causes a large increase in the rate of C-type inactivation.17 18 Accordingly, the objectives of this study were to assess the effects of the N629D HERG mutation on inactivation and ion selectivity.
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Materials and Methods |
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Expression in Xenopus Oocytes
HERG1 A in pSP64 was obtained from Dr M.T. Keating (University of Utah, Salt Lake City, Utah).2 Site-directed mutagenesis was carried out according to Ho et al.19 A dimer was constructed wherein the C terminus of N629D was linked to the N terminus of WT. The linker consisted of SGGSPS.
Currents were expressed in Xenopus oocytes and recorded
using 2-microelectrode voltage-clamp techniques.11
Oocytes were perfused with modified frog Ringer’s solution at 21°C
to 22°C containing (in mmol/L) NaCl 114, KCl 2.5,
MgCl2 1, CaCl2 1.8, and
HEPES 10, pH 7.2 adjusted with NaOH. Niflumic acid was included
(0.15 mmol/L) to block chloride currents. Glass microelectrodes
were filled with 3 mol/L KCl with tip resistances of 0.5 to 2 M
.
Oocytes were clamped with a Geneclamp 500 amplifier, and voltage-clamp
protocols were generated with pClamp software (Axon Instruments).
Currents were sampled at a rate of 2 kHz and filtered at 1 kHz using a
4-pole Bessel filter. Oocytes were held at -80 mV between pulses, with
an interpulse interval of 30 seconds. Time constants (
s) were
measured using Clampfit and s derived from Chebyshev fits to the
deactivating current using the equation
y=A0+A1e–t/1+A2e–t/2.
To express N629D homomultimers, 6 or 12 ng of RNA was injected,
for HERG1 A WT 6 ng was injected, and for coexpression studies 6 ng of
each construct was injected.
Voltage-clamp pulses used in this study are illustrated in the figures. The ramp-clamp protocol is similar to that of Chen et al,10 and the action potential clamp protocol is similar to that of Zhou et al.20 The simulated action potential clamp was modeled to that of monophasic action potentials recorded in human ventricle.21 The simulated action potential clamp duration was 250 ms. An initial pulse from a resting potential of -80 mV was followed by a transient repolarizing wave that returned the potential from +40 to 0 mV over 8 ms, followed by a plateau phase lasting 120 ms, followed by phase 3 repolarization returning from a plateau potential of 0 to -70 mV over 100 ms, followed by a terminal repolarizing phase that returned the voltage from -70 to -80 mV over 20 ms. Dofetilide-sensitive currents elicited by the action potential clamp and ramp clamps are reported.
Statistics
ANOVA was used to compare data, and the Tukey test was used for
multiple comparisons.
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Results |
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N629D Current Is Not Inwardly Rectified and Does Not Inactivate
Figure 1
shows typical currents of
WT (injected with 6 ng) in the left column and N629D (12 ng) in the
right column. Different amounts of RNA were injected to produce
currents of similar magnitude to allow appropriate comparisons. From a
holding potential of -80 mV, currents were evoked by a series of
depolarizing pulses, P1, for 2500 ms to potentials between -70 and +50
mV followed by a P2 pulse to holding of -60 mV. Tail currents of N629D
were negative over the range of voltages tested, which reflects a lack
of potassium selectivity (see below). Unlike WT currents, the N629D
current activated rapidly at all potentials and exhibited
outward rectification.
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for WT in
panel E and N629D in panel F. For N629D, the time-dependent currents
were inward over potentials from -20 to -60 mV.
Mean current-voltage relationships are shown for these examples in
Figure 1G
and 1H for WT (n=16) and N629D (n=14), respectively.
Current measured at the end of P1 was related to depolarizing
potentials (solid symbols). Inward rectification was evident for WT,
whereas outward rectification was seen with N629D. Over the potential
range from -20 to -60 mV, N629D time-dependent currents were
inward.
Na+ Carries the Inward Current of the N629D
Mutant
Figure 1 shows illustrative examples of typical currents
elicited before (Figure 1A and 1B) and after (Figure 1C and 1D) replacement of extracellular Na+
(Na+e) with extracellular
N-methyl-D-glucamine
(NMGe) for WT on the left and N629D on the right.
The inward portion of the time-dependent current and the inward tail
current of N629D were virtually abolished by replacement of
Na+e with
NMGe. Mean absolute tail current amplitude when
pulsing from +20 to -60 mV for WT was 1580±1200 nA before and
1120±480 nA (NS) after replacement of
Na+e with
NMGe, whereas for N629D the amplitude was
420±260 before and 30±6 nA after (P<0.001) replacement.
These data indicate that the inward currents of N629D are carried
predominantly by Na+e.
Activation
The mean peak of the tail current at the onset of the P2 pulse (in
open symbols) was related to the P1 potentials for WT in Figure 1G and N629D in Figure 1H (n=16 and 14, respectively).
Voltage dependence of the activated tail currents of WT were
well fit to a Boltzmann function with V1/2 for
activation of -26±7 mV (slope, 9±0.6 mV/e–fold), whereas the
V1/2 for N629D measured from inward tail current was
-37±7 mV (slope, 8±1 mV/e–fold).
N629D Channel Inward Tail Currents Deactivate More Rapidly
Than WT
N629D channel has inward tails using the protocol shown in Figure 1. Representative examples of deactivation
currents are shown for WT in Figure 1E and N629D in Figure 1F. To assess kinetics of deactivation, a double-pulse protocol
was used. The first pulse was introduced from a holding potential of
-80 mV to a potential of +50 mV for 2 seconds, followed by a second
pulse to a variety of test potentials ranging from -20 to -120 mV for
2.5 seconds. The deactivation process was fit to biexponential
functions. At -80 mV, the dominant fast component of deactivation s
for WT, 200±25 ms (n=16), were slower than that of N629D, 78±22 ms
(n=14), and at -100 mV the s were 104±20 and 41±2 ms,
respectively (P<0.01). Deactivation s of WT are similar
to those reported previously.10
N629D Alters Selectivity to K+
Figure 2 illustrates the relation
between reversal potential and
[K+]e for WT on the left
(Figure 2A) and N629D on the right (Figure 2B).
[K+]e was serially
increased from 2.5 to 5 and then to 40 mmol/L. With increases in
[K+]e, we reciprocally
decreased [Na+]e. The
plot of reversal potential versus log
[K+]e was determined by
fitting to the Goldman-Hodgkin-Katz equation. The regression line for
this plot for WT has a terminal slope of 
58 per decade, with a
best-fit permeation ratio of
[Na+]e/[K+]e
of 0.01. During replacement of
Na+e with NMG, the curve more
closely approached the Nernst slope for a pure potassium-selective
channel. In contrast, the regression line for this plot for N629D in
normal Ringer’s solution showed relatively little slope, and the
best-fit estimate of the permeation ratio
PNa/PK was 0.65.
However, during replacement of
Na+e with
NMGe, the slope of the regression line for N629D
more closely approximated that of WT with a mean
PNMG/PK of 0.03.
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) or absence (•) of
Na+e. The [K+]e was
serially increased from 2.5 to 5 and 40 mmol/L. With increases in
[K+]e, there was a reciprocal decrease in
[Na]e or [NMG]e to maintain osmolality.
Plot of the reversal potential vs log [K+]e
was determined by fitting to the Goldman-Hodgkin-Katz equation. For WT,
the best-fit permeation ratio of
[Na+]e/[K+]e was
0.01. For N629D, the best-fit estimate of the
PNa/PK was 0.65. However, during replacement of
[Na+]e with NMG, the slope of the regression
line for N629D more closely approximated that of WT, with a
PNMG/PK of 0.03.
To assess relative permeation ratio of
Cs+/K+, reversal potentials
of WT and N629D were compared in KCl and CsCl2,
both at 115 mmol/L. For WT, mean reversal potential was -37±5 in
cesium and -9±5 mV in K+ at 115 mmol/L,
whereas for N629D, the reversal potential in 115 mmol/L cesium was
-10±6 mV and in potassium it was -4±7 mV. These data indicate a
differential relative permeation ratio for cesium/potassium in HERG1 A
versus N629D. Relative permeation ratio of cesium/potassium was
evaluated according to the following formula:
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Evidence for Formation of Heteromultimers Between WT
and N629D
To assess whether functional heteromultimers of WT/N629D
are produced, response to 0
[K+]e was evaluated.
Figure 3 shows illustrative examples of
the effects of removal of all
K+e on WT in the left column,
N629D in the middle column, and the equimolar coexpressed N629D/WT in
the right column. Representative examples at 2.5
mmol/L [K+]e are shown in
the top row, at [K+]e at
0 mmol/L in the middle row, and mean responses in the bottom row.
Near elimination of outward time-dependent activating current of WT was
observed at 0 mmol/L
[K+]e, whereas no
reduction in this magnitude was observed for homomultimeric
N629D. The equimolar WT/N629D-coexpressed time-dependent current had
little response to 0 mmol/L
[K+]e. Suppose a current
was artificially produced that resulted from a superimposition of 50%
homomultimeric HERG1 A WT and 50% N629D. The resultant
superimposed current would be expected to be reduced by 50% at
[K+]e of 0 mmol/L.
As is shown in this right panel, the time-dependent current during
coexpression was reduced by 14% at 0 mmol/L
[K+]e. These data
indicate that although coexpression of WT/N629D can produce a current
with characteristics grossly similar to WT, the response of the
functional heteromultimer to
[K+]e of 0 mmol/L
cannot be explained by a superimposition of homomultimeric
currents.
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) and in 0
[K+]e (Further evidence for the formation of heteromultimers is provided by the observation that coexpression of the dominant-negative G628S HERG1 A (n=3) with N629D resulted in dominant loss of expression (data not shown). These data taken in concert provide evidence that functional heteromultimers are formed during coexpression of HERG1 A and N629D.
Physiological Significance of the N629D
Mutation
To assess the physiological significance of
N629D, action potential and ramp clamps were applied. Mean
dofetilide-sensitive currents elicited by the ramp protocol (left
panel) and the simulated action potential clamp (right panel) are shown
for homomultimeric N629D (n=6) and WT (n=6) in Figure 4. Application of these protocols
to WT resulted in only outward currents, particularly during phase 3 of
the action potential. In contrast, application of identical protocols
to N629D resulted in outward currents during the plateau of the action
potential followed by an inward current during phase 3 repolarization.
For HERG1 A, repolarization ramps result in outward repolarizing
currents, whereas for N629D, these ramps result in inward depolarizing
currents at voltages more negative than -20 mV (Figure 4D).
These data indicate that the loss of potassium selectivity results in
inward depolarizing currents during phase 3 of this artificial action
potential.
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In Figure 5, the upper row
shows the spectrum of phenotypes observed after injection of
equimolar concentrations of WT and N629D. The left column shows a
family of currents that is intermediate between N629D and WT, with no
inward tail and a reversal potential of -58 mV. The middle column
shows an N629D-like phenotype. An inward tail current is
apparent, and the reversal potential of the tail currents is -8 mV.
The right column shows a WT-like phenotype, in that it has an
outward tail current and the reversal potential is -78 mV. Of 44
oocytes injected, 12 had a phenotype similar to that in the
left panel (intermediate phenotype), 11 similar to the middle
panel (N629D-like), and 21 similar to the right panel (WT-like). Mean
reversal potential of oocytes expressing the intermediate
phenotype was -56±9 mV; that of the N629D-like
phenotype was -6±4 mV, and that of the WT-like
phenotype was -82±6 mV. In contrast, the mean reversal
potential of WT was -90±3 mV (P<0.05 by ANOVA).
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In contrast to the variability of phenotypes observed when equimolar concentrations are injected, consistent phenotypes are observed when 3-fold excesses of WT or N629D are injected. When WT is injected in 3-fold excess, all measured currents have a phenotype similar to WT, whereas when N629D is injected in 3-fold excess the phenotype is consistently similar to homomultimeric N629D.
To further assess the physiological significance of
N629D coexpressed with WT at equimolar concentrations, the same action
potential and ramp clamps were applied. Representative
examples of dofetilide-sensitive currents elicited by the ramp protocol
are shown in the middle row of panels in Figure 5 and those of
the simulated action potential clamp are shown in the lower row of
panels for the various phenotypes seen during coexpression.
Coexpressed current shown in the dotted lines is contrasted with WT
shown in the solid lines. Application of these protocols to WT results
in outward currents, particularly during phase 3 of the action
potential. In contrast, application of identical protocols to
coexpressed currents with the intermediate and N629D-like
phenotype resulted in inward currents during phase 3
repolarization. In contrast, oocytes with WT-like phenotype
manifest reduced repolarizing currents during phase 3 of the action
potential.
To assess phenotype of a HERG tetramer with known ratio
of WT and N629D subunits, a dimer of N629D connected at its C-terminal
end to the N terminus of WT was constructed. Injection of this dimer
generated currents that had characteristics intermediate between WT and
N629D (Figure 6); moreover, the resultant
current showed no variability in phenotype from oocyte to
oocyte.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Potential Clinical Relevance
The consequences of the N629D mutation are a loss of C-type inactivation and cation selectivity. Disruption of C-type inactivation results in elimination of the outward tail current that would normally result from recovery of inactivated channels during repolarization. Loss of this outward tail current may be a key determinant of disease phenotype, as it is important in the later phase of repolarization and is thought to be involved in prevention of arrhythmias.22 23 A novel property of N629D is a severe loss of selectivity of K+ relative to Na+, which manifests as an inward Na+ current at membrane potentials below -20 mV. Our action potential clamp data suggest that an inward depolarizing Na+ current will be produced during repolarization between -20 and -70 mV. Such a late inward Na+ current is analogous to mutations found in LQT3 in which inactivation of the cardiac sodium channel is delayed, resulting in a sustained inward Na+ current.24
A limitation of this and all previous studies utilizing mammalian cell lines or Xenopus oocytes to characterize LQT mutations is that they may not represent the exact phenotype that occurs in cardiac myocytes.
Heteromultimers Have Variable Phenotypes
Given that N629D and WT express as homomultimers, it might
be expected that heteromultimers would form. We provide
evidence that functional heteromultimers are formed by
assessing response of homomultimers and coexpression channels
to 0 mmol/L [K+]e.
The time-dependent current of HERG is markedly reduced at 0 mmol/L
[K+]e, whereas that of
homomultimeric N629D is unaffected. Coexpression of monomers
produces currents that can appear grossly similar to that of WT,
including outward tail currents and inward rectification. However,
these coexpressed currents were reduced by only 14% when exposed to 0
[K+]e compared with the
expected value of 50%. Thus, these data cannot be explained by a
superimposition of WT and N629D homomultimeric currents.
When N629D is coexpressed at equal concentrations with WT, phenotypes range from N629D-like, intermediate, and WT-like. This unusual phenomenon may have resulted, despite our best efforts, from incomplete mixing of mRNAs. Alternatively, physiochemical differences between oocytes may result in differences in ability to correctly fold and/or incorporate the mutant channel into tetramers. To better understand this phenomenon, we constructed a dimer with a N629D monomer linked to a WT monomer. The resultant current shows no variability in phenotype from oocyte to oocyte, and the phenotype is intermediate between WT and N629D. We speculate that small differences in gene expression or cell physiology may lead to a diversity of phenotypes between individuals or between cells. If our data can be extrapolated from oocytes to heart, intercell diversity in phenotypes could contribute to spatially heterogeneous repolarization that is reported in patients with LQT2.25
In summary, the N629D mutation exerts its effect through removal of C-type inactivation and a reduction in selectivity for K+e over Na+e. This results in a decrease in the outward repolarizing tail current that is replaced with an inward depolarizing sodium current, which is expected to cause a delay in the later stages of repolarization and contribute to arrhythmogenesis.
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Acknowledgments |
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This study was supported by the Medical Research Council of Canada, the Alberta Heart and Stroke Foundation, and the Andrews Family Professorship in Cardiovascular Science. We thank Drs Robert Clark and Robert French for constructive help and suggestions.
Received September 13, 1999; accepted December 22, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 Y. Lu, M. P Mahaut-Smith, C. L-H Huang, and J. I Vandenberg Mutant MiRP1 subunits modulate HERG K+ channel gating: a mechanism for pro-arrhythmia in long QT syndrome type 6 J. Physiol., August 15, 2003; 551(1): 253 - 262. [Abstract] [Full Text] [PDF]
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P. Hajdu, C. Ulens, G. Panyi, and J. Tytgat Drug- and mutagenesis-induced changes in the selectivity filter of a cardiac two-pore background K+ channel Cardiovasc Res, April 1, 2003; 58(1): 46 - 54. [Abstract] [Full Text] [PDF]
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G. Q. Teng, J. P Lees-Miller, Y. Duan, B.-T. Li, P. Li, and H. J Duff [K+]o-dependent change in conformation of the HERG1 long QT mutation N629D channel results in partial reversal of the in vitro disease phenotype Cardiovasc Res, March 1, 2003; 57(3): 642 - 650. [Abstract] [Full Text] [PDF]
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 A. Paulussen, A. Raes, G. Matthijs, D. J. Snyders, N. Cohen, and J. Aerssens A Novel Mutation (T65P) in the PAS Domain of the Human Potassium Channel HERG Results in the Long QT Syndrome by Trafficking Deficiency J. Biol. Chem., December 6, 2002; 277(50): 48610 - 48616. [Abstract] [Full Text] [PDF]
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E. C. R. Roti, C. D. Myers, R. A. Ayers, D. E. Boatman, S. A. Delfosse, E. K. L. Chan, M. J. Ackerman, C. T. January, and G. A. Robertson Interaction with GM130 during HERG Ion Channel Trafficking. DISRUPTION BY TYPE 2 CONGENITAL LONG QT SYNDROME MUTATIONS J. Biol. Chem., November 27, 2002; 277(49): 47779 - 47785. [Abstract] [Full Text] [PDF]
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S. Rajamani, C. L. Anderson, B. D. Anson, and C. T. January Pharmacological Rescue of Human K+ Channel Long-QT2 Mutations: Human Ether-a-Go-Go-Related Gene Rescue Without Block Circulation, June 18, 2002; 105(24): 2830 - 2835. [Abstract] [Full Text] [PDF]
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K. Hayashi, M. Shimizu, H. Ino, M. Yamaguchi, H. Mabuchi, N. Hoshi, and H. Higashida Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome Cardiovasc Res, April 1, 2002; 54(1): 67 - 76. [Abstract] [Full Text] [PDF]
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E. Ficker, C. A. Obejero-Paz, S. Zhao, and A. M. Brown The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations J. Biol. Chem., February 8, 2002; 277(7): 4989 - 4998. [Abstract] [Full Text] [PDF]
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C. E. Clancy and Y. Rudy Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 301 - 313. [Abstract] [Full Text] [PDF]
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 U. C. Hoppe, E. Marban, and D. C. Johns Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1 PNAS, April 24, 2001; 98(9): 5335 - 5340. [Abstract] [Full Text] [PDF]
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A. A. M. Wilde and D. M. Roden Predicting the Long-QT Genotype From Clinical Data : From Sense to Science Circulation, December 5, 2000; 102(23): 2796 - 2798. [Full Text] [PDF]
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G. A. Robertson LQT2 : Amplitude Reduction and Loss of Selectivity in the Tail That Wags the HERG Channel Circ. Res., March 17, 2000; 86(5): 492 - 493. [Full Text] [PDF]
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