Long QT Syndrome-associated Mutations in the Per-Arnt-Sim
(PAS) Domain of HERG Potassium Channels Accelerate Channel
Deactivation*
Jun
Chen
,
Anrou
Zou
,
Igor
Splawski§¶,
Mark
T.
Keating
§¶, and
Michael C.
Sanguinetti
**
From the
Department of Medicine, Division of
Cardiology,
Eccles Program in Human Molecular Biology and
Genetics, § Howard Hughes Medical Institute, and
¶ Department of Genetics, University of Utah,
Salt Lake City, Utah 84112
 |
ABSTRACT |
Mutations in the human
ether-a-go-go-related gene (HERG) cause long QT
syndrome, an inherited disorder of cardiac repolarization that
predisposes affected individuals to life-threatening arrhythmias. HERG encodes the cardiac rapid delayed rectifier potassium
channel that mediates repolarization of ventricular action potentials. In this study, we used the oocyte expression system and voltage clamp
techniques to determine the functional consequences of eight long QT
syndrome-associated mutations located in the amino-terminal region of
HERG (F29L, N33T, G53R, R56Q, C66G, H70R, A78P, and L86R). Mutant
subunits formed functional channels with altered gating properties when
expressed alone in oocytes. Deactivation was accelerated by all
mutations. Some mutants shifted the voltage dependence of channel
availability to more positive potentials. Voltage ramps indicated that
fast deactivation of mutant channels would reduce outward current
during the repolarization phase of the cardiac action potential and
cause prolongation of the corrected QT interval, QTc. The
amino-terminal region of HERG was recently crystallized and shown to
possess a Per-Arnt-Sim (PAS) domain. The location of these mutations
suggests they may disrupt the PAS domain and interfere with its
interaction with the S4-S5 linker of the HERG channel.
 |
INTRODUCTION |
Mutations in the human ether-a-go-go-related gene
(HERG)1 cause LQT,
an inherited disorder of cardiac repolarization (1-10). HERG encodes a potassium channel with properties nearly
identical to IKr of cardiac myocytes (11, 12).
Mutations in HERG can reduce IKr by loss of
function, altered function, or a dominant negative effect (8, 13, 14).
Reduction of IKr causes delayed myocyte
repolarization (15) and an increased risk of life-threatening ventricular arrhythmia (16).
The combination of two properties, fast inactivation and slow
deactivation, distinguish IKr from other cardiac
currents (15). HERG channels inactivate much more rapidly than they
activate. The net result is that most HERG channels are closed during
the plateau phases of the cardiac action potential. Rapid recovery from
inactivation during repolarization combined with a very slow subsequent
transition to the closed state (deactivation) results in an increase of
IKr during the terminal phase of cardiac
repolarization. The structural basis of rapid inactivation and slow
deactivation of HERG is partially understood. Inactivation can be
completely removed by a double mutation in the pore region of the
channel (17), indicating the importance of this region and its
similarity to C-type inactivation (18, 19). This mechanism is in
contrast to most rapidly inactivating K+ channels in which
interaction of the amino terminus with the S4-S5 linker closes the
channel by occlusion of the inner pore region (20). HERG channel
deactivation is greatly accelerated by removal of the amino-terminal
region or by mutation of specific residues in the S4-S5 linker (21,
22). The crystal structure of the amino-terminal region of HERG has
been determined and shown to possess a Per-Arnt-Sim (PAS) domain (23).
This domain may interact with another region of HERG such as the S4-S5
linker to affect channel deactivation.
A negative shift in the voltage dependence of inactivation or
acceleration in the rate of deactivation would reduce the contribution of IKr to repolarization and lengthen the
duration of cardiac action potentials. Mutations in HERG that cause LQT
and shift the voltage dependence of inactivation have been described
(8). In this study, we describe several LQT-associated mutations in the
amino-terminal region of HERG that accelerate the rate of deactivation.
The location of these mutations in the recently described
three-dimensional structure of the HERG amino-terminal region (23)
suggests they may disrupt the function of the PAS domain.
 |
EXPERIMENTAL PROCEDURES |
Construction of HERG Mutations and in Vitro Transcription of
cRNA--
Mutations were introduced into wild type (WT) HERG by the
megaprimer method (24). The mutant construct was then subcloned into
the pSP64 (Promega, Madison, WI) plasmid expression vector. Before use
in expression experiments, the constructs were characterized by
restriction mapping and DNA sequence analyses. cRNA for injection into
oocytes were prepared with SP6 Capscribe (Boehringer Mannheim) following linearization with EcoRI.
Isolation of Oocytes and Injection of
RNA--
Xenopus laevis frogs were anesthetized
by immersion in 0.2% tricaine for 15-30 min. Ovarian lobes were
digested with 2 mg/ml Type 1A collagenase (Sigma) in
Ca2+-free ND96 solution for 1.5 h to remove follicle
cells. Stage IV and V oocytes were injected with HERG cRNA (7.5 ng),
then cultured in Barth's solution supplemented with 50 µg/ml
gentamycin and 1 mM pyruvate at 18 °C. Barth's solution
contained 88 mM NaCl, 1 mM KCl, 0.4 mM CaCl2, 0.33 mM
Ca(NO3)2, 1 mM MgSO4,
2.4 mM NaHCO3, 10 mM HEPES, pH
7.4.
Voltage Clamp of Oocytes--
Oocytes were bathed in a modified
ND96 solution containing 96 mM NaCl, 2 mM KCl,
2 mM MgCl2, 0.1 mM
CaCl2, 5 mM HEPES, pH 7.6. Currents were
recorded at room temperature (21-23 °C) using standard
two-microelectrode voltage clamp techniques (25). Glass microelectrodes
were filled with 3 M KCl, and their tips were broken to
obtain tip resistances of 0.5-1.5 M
. Oocytes were
voltage-clamped with a Dagan TEV-200 amplifier (Dagan Corp.,
Minneapolis, MN). Voltage commands were generated using pCLAMP software
(Axon Instruments, Foster City, CA), a personal computer, and a TL-1
D/A interface (Axon Instruments). Unless noted otherwise, the oocyte
membrane potential was held at
80 mV between test pulses.
PCLAMP6.2 software was used to fit current traces to exponential
functions. Exponential fits to current tracings were performed using
the Chebyshev technique to determine the time constants (
x) and amplitudes (AX) for
exponential functions. The voltage dependence of HERG activation was
determined from tail currents measured at -70 mV following 2- or 30-s
test depolarizations. Normalized tail current amplitude
(In) was plotted versus test potential
(Vt) and fitted to a Boltzmann function using ORIGIN
(Northampton, MA),
|
(Eq. 1)
|
V1/2 is the voltage at which the current
is half-activated, and k is the slope factor. The voltage
dependence of HERG inactivation was determined using a three-pulse
voltage pulse protocol as described previously (26). The peak of the
inactivating current during the third pulse was normalized to the peak
value, plotted as a function of the voltage of the second pulse, then
fitted with a Boltzmann function. Data are expressed as the mean ± S.E.(n = number of oocytes).
 |
RESULTS |
Identification of Long QT-associated Mutations in HERG--
The
amino-terminal region is a highly conserved domain in all members of
the eag potassium channel family that includes eag, erg, and elk. We
and others (21, 22, 27) previously reported that expression of HERG
channels lacking this domain deactivate much faster than WT HERG
channels, indicating the importance of this domain in normal gating. We
hypothesized missense mutations within this domain that cause LQT would
also accelerate deactivation and thereby reduce outward current through
HERG channels during repolarization of the cardiac action potential.
After solving the genomic structure of HERG (9), we used
single strand conformation polymorphism and DNA sequence analyses to
screen for mutations in individuals with LQT. Many mutations were found
in the amino-terminal region of
HERG.2 Eight missense
mutations located in the amino-terminal region of HERG were chosen for
electrophysiologic characterization (F29L, N33T, G53R, R56Q, C66G,
H70R, A78P, and L86R). These mutations are located near the end of the
amino terminus of HERG, which is about 400 amino acids in length.
Biophysical Characterization of Mutant HERG Channels--
Mutant
channels were constructed using site-directed mutagenesis. cRNA for
each construct was prepared and injected into Xenopus oocytes. Voltage clamp experiments were performed to assess the functional consequences of each mutation. Unlike the majority of
LQT-associated missense mutations in HERG (13, 14, 29), the 8 amino-terminal mutant HERG subunits formed functional channels when
expressed alone in Xenopus oocytes. The I-V relationship for
each oocyte was determined by pulsing to +40 mV for 1 s to allow
currents to reach a steady-state level before repolarization for 3 s to a potential ranging from +40 to -120 mV (Fig.
1A). The currents at the end
of the 3-s pulse were plotted as a function of voltage (Fig.
1B). The I-V relationships indicate that WT HERG and mutant
HERG channels exhibit weak inward rectification. The peak of the I-V
for some of the mutant HERG channels was shifted in the positive
direction. As discussed below, this shift can be explained by an
altered voltage dependence of channel inactivation.

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Fig. 1.
I-V relationships of WT HERG and mutant HERG
channels exhibit similar rectification. A, H70R HERG
currents recorded during test pulses to potentials ranging from 120
to +40 mV, applied in 20-mV increments after a 1-s activating pulse to
+40 mV. B, I-V relationships for WT and mutant HERG channels
(n = 6-7). Currents were measured at the end of the
3-s test pulse. , WT; , F29L; , R56Q; , G53R; , N33T;
, L86R; , H70R; , A78P; , C66G HERG.
|
|
The most notable change caused by the mutations was an accelerated rate
of current deactivation. Fig.
2A shows tail currents for WT
HERG and three mutants elicited by a similar voltage pulse protocol
illustrated in Fig. 1. The rate of current deactivation was determined
by fitting tail currents to a two-exponential function at potentials
ranging from -70 mV to -120 mV for WT HERG and from -50 mV to -120
mV for the mutant channels. Deactivation was too slow to measure during
the 3-s period at -50 mV and -60 mV for WT HERG channels. All 8 mutant HERG channels deactivated more rapidly than WT HERG channels at
potentials positive to -90 mV. The rate of deactivation varied for
each mutant and was fastest for R56Q HERG and slowest for H70R HERG.
For example, at -70 mV, WT HERG channels deactivated with time
constants of 0.42 s and 1.90 s. By contrast, the mutant
channels had time constants that ranged from 0.067 to 0.22 s for
the fast component and 0.18 to 1.20 s for the slow component (Fig.
2, B and C). The rate of HERG channel activation
between -40 mV and 0 mV was best described with a two-exponential
function. The rates of activation were similar for WT HERG and most of
the mutant HERG channels. The exceptions were R56Q and N33T, which
activated more slowly than WT HERG (Fig.
3).

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Fig. 2.
Mutations in the amino-terminal domain of
HERG accelerate deactivation. A, pulse protocol and currents
recorded from oocytes expressing WT HERG (top panel) and
three of the mutant HERG channels (lower 3 panels). Tail
currents were fitted with two exponential function. B and
C, voltage-dependent time constants for fast
(B) and slow (C) components of deactivation
(n = 8-16). , WT; , F29L; , R56Q; , G53R;
, N33T; , L86R; , H70R; , A78P; , C66G HERG.
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Fig. 3.
Voltage dependence of HERG activation rate.
A, activating currents for WT HERG and N33T HERG were fitted
with two exponential functions, and the fitted traces were superimposed
over current traces. B and C,
voltage-dependent time constants for fast (B)
and slow (C) components of activation (n = 8-10). N33T and R56Q HERG channels activated slower than WT HERG
channels. , WT; , F29L; , R56Q; , G53R; , N33T; ,
L86R; , H70R; , A78P; , C66G HERG.
|
|
The voltage dependence of steady-state activation was determined for
several mutants (N33T, R56Q, H70R, L86R) by measuring the relative
amplitude of tail currents measured at -70 mV after a 30-s-activating
pulse to potentials ranging from -70 to 0 mV (Fig.
4A). These mutants were chosen
because they caused the greatest changes in kinetics or shifts in the
voltage dependence of the I-V relationship. The
V1/2 and slope factor for WT HERG was
-52.1 ± 0.6 mV and 6.7 ± 0.3 mV (n = 7).
The V1/2 for H70R and L86R HERG channels were
similar to WT, but the V1/2 was shifted by +7.6
mV for N33T HERG and +11.3 mV for R56Q HERG (Fig. 4B and 6B).

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Fig. 4.
Voltage dependence of steady-state HERG
activation. A, pulse protocol and example of WT HERG
currents during 30-s depolarization to potentials ranging from 70 to
0 mV. B, relative tail currents for WT ( ), N33T ( ),
H70R ( ), L86R ( ) HERG currents were fit with a Boltzmann function
to determine half-point (V1/2) and slope factor
(k) for each channel type. WT (n = 7):
V1/2 = 52 ± 0.6 mV, k = 6.7 ± 0.3 mV; N33T (n = 4):
V1/2 = 44.5 ± 0.6 mV, k = 6.8 ± 0.3 mV; H70R (n = 4):
V1/2 = 53.6 ± 0.6 mV, k = 10.4 ± 0.6 mV; L86R (n = 6):
V1/2 = 50.3 ± 0.6 mV, k = 8.1 ± 0.6 mV.
|
|
The voltage dependence of channel availability was determined using a
three-pulse protocol described previously (17, 26). A 1-s pulse to +35
mV to inactivate most channels was followed by a 20-ms pulse to a
variable potential (
145 to +35 mV) to allow a variable recovery of
channels from inactivation but little or no deactivation. The third
pulse was to +35 mV to assess the relative number of channels that
recovered from inactivation during the second pulse (Fig.
5A). The peak current elicited
by the third pulse was estimated by extrapolation of a single
exponential fit of the current trace to the beginning of the pulse.
These data were plotted as a function of the voltage for pulse two and
then fit with a Boltzmann function to determine the peak current to be
used for normalization. The normalized data was averaged and fit with a
Boltzmann function to determine the V1/2 and
slope factor of the relationship (Fig. 5B). For these
experiments, we characterized the four mutants that caused the greatest
positive shift in the peak of the steady-state I-V relationship. The
V1/2 for the voltage dependence of steady-state
channel availability was -89.3 mV for WT HERG channels. All four
mutants (N33T, R56Q, H70R, L86R) caused a positive shift in this
relationship. The V1/2 was shifted by +19.6 mV
for N33T, +9.5 mV for H70R, +9.0 mV for L86R (Fig. 5B), and
+35.8 mV for R56Q HERG (Fig.
6C). The slope factor of the
relationship was not significantly altered by any of the mutant
channels. The shift in the voltage dependence of channel availability
explains the shift in the peak of the steady-state I-V relationship
shown in Fig. 1.

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Fig. 5.
Voltage dependence of channel availability
for WT and 3 mutant HERG channels. A, example of WT HERG
currents during three-pulse protocol used to estimate voltage
dependence of inactivation. The upper panel shows voltage
pulse protocol; the lower panel shows expanded view of
currents highlighted by arrows in the upper
panel. Inactivating currents during the final pulse were fitted to
a single exponential function and extrapolated to the start of
depolarization to estimate initial current. B, relative peak
currents for WT ( ), N33T ( ), H70R ( ), L86R ( )HERG currents
were fit with a Boltzmann function to determine half-point
(V1/2) and slope factor (k) for each channel
type. WT (n = 10): V1/2
= 89.3 ± 1.7 mV, k = 23.1 ± 0.8 mV; N33T
(n = 5): V1/2 = 69.7 ± 4.4 mV, k = 21.6 ± 0.2 mV; H70R
(n = 9): V1/2 = 79.8 ± 2.2 mV, k = 22.7 ± 0.7 mV; L86R
(n = 6): V1/2 = 80.3 ± 2.4 mV, k = 22.7 ± 0.7 mV.
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Fig. 6.
Currents induced by coexpression of WT HERG
and R56Q HERG subunits have properties intermediate to that induced by
either subunit alone. A, examples of currents during
depolarizations from -70 to 0 mV for oocytes expressing WT, R56Q, and
WT + R56Q HERG channels. B, voltage-dependent
activation of WT ( , same as Fig. 4), R56Q ( ,
V1/2 = 40.8 ± 2.2 mV, k = 6.9 ± 0.3 mV, n = 6), and R56Q + WT HERG ( ,
V1/2 = 44.7 ± 0.9 mV, k = 7.3 ± 0.3 mV, n = 7). C, voltage
dependence of channel availability for WT (same as Fig. 5), R56Q
(V1/2 = 53.5 ± 1.3 mV, k = 25.3 ± 1.0 mV, n = 8), and R56Q + WT HERG
(V1/2 = 70.4 ± 2.4 mV, k = 27.6 ± 1.0 mV, n = 10). D, fast
deactivation of R56Q HERG channels reduces amplitude of current during
repolarization phase of a voltage ramp. Currents were normalized to
amplitude of instantaneous tail currents at 120 mV to account for
variable levels of channel expression between individual oocytes.
Instantaneous tail current was measured by extrapolation of the
deactivating phase to the time of initial repolarization from a
prepulse to +40 mV. The traces represent the mean current
for 5 oocytes + or - 1 S.E. (n = 5 for each
trace).
|
|
The mutations of HERG studied here are inherited in a dominant manner.
Thus, affected individuals have one normal allele and one mutant
allele. To mimic the disease condition, the currents induced by
coexpression of WT HERG subunits and one of the mutant subunits (R56Q)
were compared with currents induced by expression of WT HERG or R56Q
HERG subunits alone. Coexpression of R56Q HERG and WT HERG subunits
resulted in a current that was similar or larger in magnitude compared
with WT HERG alone but had intermediate kinetics of deactivation and
voltage dependence of activation (Fig. 6A). For example, at
-70 mV, the time constants for deactivation were 0.42 s and
1.90 s for WT HERG, 0.067 s and 0.18 s for R56Q HERG, and
0.11 s and 0.58 s for cells expressing WT + R56Q HERG channel
subunits. The shift in the V1/2 for steady-state
activation induced by coexpression of WT and R56Q HERG channel subunits
was +7.4 mV, about half that caused by R56Q HERG alone (Fig.
6B). As shown in Fig. 6C, the shift in the
voltage dependence of channel availability induced by R56Q HERG (+35.8
mV) was about twice that measured for oocytes expressing WT + R56Q HERG
subunits (+18.9 mV). These data indicate that R56Q HERG does not have a
dominant negative effect when coexpressed with WT HERG but does alter
the kinetics and voltage dependence of heteromultimeric channels.
To simulate the voltage transition that occurs during a cardiac action
potential, we applied a voltage step from -80 mV to +40 mV followed by
a slow (1.7 s) voltage ramp back to -80 mV. Although this voltage
protocol does not accurately simulate a ventricular action potential,
it is useful to demonstrate the gradual increase then decrease in
current magnitude during membrane repolarization. The amplitude of
current during the declining voltage ramp is determined by (1) the
number of channels that recover from inactivation, which increases
current magnitude, (2) the declining driving force for outward flux of
K+, and (3) the rate of channel deactivation, which
decreases current magnitude. The voltage dependence of channel
availability (Fig. 6C) is the only important determinant of
the number of channels that recover from inactivation because the rate
of recovery from inactivation is extremely fast (11). Because R56Q HERG
caused the greatest shift in channel availability (Fig. 6C)
and rate of deactivation (Fig. 2), we compared the current induced by
voltage ramps for this mutant with WT HERG. As shown in Fig.
6D, R56Q HERG current is initially larger than WT HERG
current. However, later in the voltage ramp, corresponding to voltages
negative to -48 mV, WT HERG current is larger than R56Q HERG current.
The ramp current recorded in oocytes that were coinjected with cRNA for
WT and R56Q HERG subunits was intermediate in magnitude to oocytes
expressing either WT or R56Q HERG alone. These data indicate that
although the R56Q HERG current activated during step depolarizations can be larger than WT HERG because of the positive shift in the voltage
dependence of channel availability, the rapid deactivation caused by
this mutation results in a smaller current when the membrane is slowly repolarized.
 |
DISCUSSION |
Mutations in HERG that cause LQT can reduce the amplitude of
IKr by several different mechanisms. The most
common mechanism is a loss of channel function and a dominant negative
effect when mutant subunits are coexpressed with WT HERG subunits. Loss
of function can result from an alteration of a critical structural component, exemplified by mutations in the pore region of HERG (13,
14), or abnormal channel processing (14). Frameshift or deletion
mutations that cause truncation of the encoded protein can cause
haplo-insufficiency without a dominant-negative effect (13). Only a few
LQT-associated HERG mutants encode proteins that can form functional
channels when expressed alone in a heterologous expression system (8,
13, 30). We have found that eight LQT-associated missense mutations in
the amino terminus of HERG channels form functional channels with
altered properties when expressed alone in oocytes. These mutations
cause an accelerated rate of channel deactivation. This alteration in
gating reduces outward current through HERG channels during
repolarization from the plateau phase of the cardiac action potential,
prolongs the QTc interval, and is the likely cause of
the increased risk of torsades de pointes arrhythmia in affected
individuals (16).
Nakajima et al. (8) recently reported on the functional
consequences of two LQT-associated missense mutations in HERG (V630L, A614V) that cause loss of function. These mutants suppressed current by
a dominant negative effect and by altering properties of inactivation when coexpressed with WT HERG subunits. These mutant residues are
located in the outer mouth of the channel pore, a region known to be an
important determinant of fast C-type inactivation of HERG channels
(17). Both mutant subunits enhanced inactivation by causing a negative
shift in the voltage dependence of channel availability when
coexpressed with WT HERG subunits. This effect would increase channel
rectification and reduce repolarizing current during an action
potential and prolong action potential duration and the QTc
interval. Surprisingly, we found that several missense mutations in the
amino-terminal domain of HERG shifted the voltage dependence of channel
availability in the positive direction. In the absence of any other
effect, this shift would cause an increase in outward current during
repolarization and, inferentially, a decrease in QTc
interval. However, these mutations also accelerated the rate of channel
deactivation, an affect that dominates the shift in channel
availability and would cause a net reduction in outward current during
slow repolarization typical of a cardiac action potential. This effect
is exemplified by R56Q, the mutation that caused the greatest shift in
the voltage dependence of channel availability (+36 mV) and the most
pronounced increase (7- to 10-fold at -70 mV) in the rate of
deactivation (Fig. 2).
The altered channel deactivation properties caused by mutations in the
amino-terminal region of HERG indicate the important role of this
domain in gating. The crystal structure of this domain was recently
solved and shown to be a PAS domain (23). PAS domains are basic
helix-loop-helix structures that have been shown to be the site of
protein-protein interactions for factors that function in sensing and
signal transduction. Examples include PAS-mediated dimerization of the
transcription factors trachealless (Trh) with single-minded (Sim) (31),
the transcription factors PER with TIM (32), and the dioxin receptor
with the basic helix-loop-helix PAS factor Arnt (33, 34). Sensing
proteins with a PAS domain include photoactive yellow protein that
senses light in bacteria (35). Although the interactive regions in
these PAS domains are understood, it is unclear how the PAS domain of
HERG modulates channel gating. Physiologic studies suggest that this
domain may interact with the S4-S5 linker of the same channel. Removal
of the amino-terminal region of HERG channels accelerates deactivation (21, 22). Alternatively spliced variants of erg channels that lack a
portion of the amino-terminal domain also exhibit fast deactivation
(36, 37). Missense mutations or chemical modification of the S4-S5
linker of HERG mimic the effects of amino-terminal deletion on channel
deactivation (28, 38). Similar interactions have been noted in the eag
channel, which also contains the same PAS domain in the amino terminus
(27). Deletion of amino acids 2-12 from HERG speeds deactivation but
has no effect on inactivation gating (38). Removal of a larger portion
of the amino-terminal region (residues 2-354) also shifts the voltage
dependence of inactivation to more positive potentials (21) and slows
the rate of C-type inactivation (38). Our studies indicate that mutation of a single residue (i.e. R56Q) can alter the
gating of both deactivation and inactivation. Thus, it appears that the amino-terminal region of HERG slows deactivation by binding to the
S4-S5 linker. The mechanism by which this interaction affects inactivation is unknown.
F29L, N33T, G53R, R56Q, C66G, and L86R are conserved in all known erg,
eag, and elk channels, emphasizing their critical role for normal
channel function. The functional effect of a mutation in this region
has been studied previously. Morais Cabral et al. (23)
reported that the mutation F29A HERG sped the rate of deactivation the
most of any missense mutation by a factor of about two. Deletion of
residues 2-9 had a similar effect, and further deletion (
2-26) was
as effective as complete truncation of the amino terminus. In general,
all the mutations studied here are likely to disrupt the structural
integrity of the PAS domain and alter its required interaction with the
rest of the channel to modulate deactivation.
In summary, LQT-associated mutations in HERG accelerate the rate of
channel deactivation. It is likely that this effect is caused by
disruption of the interaction of the amino-terminal domain with the
S4-S5 linker of HERG subunits, which normally slows the gating
associated with channel deactivation. The increased rate of channel
deactivation decreases the contribution of HERG current to cardiac
repolarization, resulting in prolongation of ventricular action
potentials and predisposes affected individuals to life-threatening arrhythmias.
 |
ACKNOWLEDGEMENTS |
The technical support of M. Lin and M. Martines is gratefully acknowledged.
 |
FOOTNOTES |
*
This work was supported by Grants HL52338 and HL55236 from
the National Heart, Lung, and Blood Institute and a grant-in-aid from
the American Heart Association.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 North 2030 East, Rm. 4220, Salt
Lake City, UT 84112. Tel.: 801-585-6336; Fax: 801-585-3501; E-mail:
mike.sanguinetti{at}hci.utah.edu.
2
Splawski, I., and Keating, M. T., submitted
for publication.
 |
ABBREVIATIONS |
The abbreviations used are:
cRNA, complementary
RNA;
HERG, human ether-a-go-go-related gene;
I-V, current-voltage;
IKr, rapid delayed rectifier
K+ current;
LQT, long QT syndrome;
PAS, Per, Arnt, and Sim;
QTc, corrected QT interval;
WT, wild-type.
 |
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