(Circulation. 2000;101:54.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Cardiac Na+ Channel Dysfunction in Brugada Syndrome Is Aggravated by ß1-Subunit
From the Department of Cardiovascular Medicine (N.M., N.S., K.S., A.K.) and Department of Pharmacology (M.K.), Hokkaido University School of Medicine, Sapporo, Japan, and the Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine (D.W.W., A.L.G.), Nashville, Tenn.
Correspondence to Naomasa Makita, MD, PhD, Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-8638, Japan. E-mail makitan{at}med.hokudai.ac.jp
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Abstract |
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Background—Mutations in the gene encoding the human cardiac Na+ channel
-subunit (hH1)
are responsible for chromosome 3–linked congenital long-QT syndrome
(LQT3) and idiopathic ventricular fibrillation (IVF). An
auxiliary ß1-subunit, widely expressed in excitable
tissues, shifts the voltage dependence of steady-state inactivation
toward more negative potentials and restores normal gating kinetics of
brain and skeletal muscle Na+ channels expressed in
Xenopus oocytes but has little if any functional effect
on the cardiac isoform. Here, we characterize the altered effects of a
human ß1-subunit (hß1) on the
heterologously expressed hH1 mutation (T1620M) previously associated
with IVF. Methods and Results—When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V1/2) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of hß1 did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V1/2 and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal.
Conclusions—It is suggested that coexpression of
hß1 exposes a more severe functional defect that results
in a greater overlap in the relationship between channel inactivation
and activation (window current) in T1620M, which is proposed to be a
potential pathophysiological mechanism of IVF in
vivo. One possible explanation for our finding is an altered
-/ß1-subunit association in the mutant.
Key Words: action potentials • arrhythmia • death, sudden • electrophysiology • fibrillation
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Introduction |
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Idiopathic ventricular fibrillation (IVF) is a clinical disorder characterized by development of ventricular fibrillation without obvious structural heart disease. It is believed to account for 3% of survivors of out-of-hospital cardiac arrest.1 In 1992, Brugada and Brugada2 described 8 patients with unique ECG findings consisting of right bundle-branch block and ST-segment elevation in leads V1 through V3, normal Q-T interval, and aborted cardiac death. This is now called the Brugada syndrome and represents a distinct syndrome of IVF. The clinical features of the Brugada syndrome can be attributed to early repolarization, depolarized areas of right ventricular myocardium, or focal right ventricular conduction abnormalities.3
Recent genetic studies have confirmed that the Brugada syndrome and
chromosome 3–linked congenital long-QT syndrome (LQT3) are allelic
disorders of the cardiac Na+ channel -subunit
gene (SCN5A, 3p21).4 5 At present, 3
SCN5A mutations have been demonstrated in the Brugada
syndrome: a splice-donor mutation, a frame-shift mutation, and a
missense mutation.5 The missense mutation, T1620M,
results in substitution of methionine for Thr1620 located at the
extracellular linker between segments S3 and S4 of domain 4 (D4/S3-S4)
of the human cardiac Na+ channel -subunit
(hH1)6 (Figure 1
). T1620M
mutant channels expressed in Xenopus oocytes showed a shift
of voltage dependence of steady-state inactivation toward more positive
potentials and 20% to 30% acceleration of recovery from
inactivation.5 Persistent currents due to channel
reopening, a molecular basis for QT prolongation in
LQT3,7 8 9 were not evident in T1620M.5 It is
not clear, however, whether these rather subtle functional defects of
T1620M are sufficient to cause ECG abnormalities and predisposition to
lethal ventricular arrhythmias in Brugada syndrome
patients or whether some other factors involved in the functional
association with mutant channel molecules may give rise to aggravation
of the biophysical abnormality in vivo.
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) and LQT3 mutations (•). Four hydrophobic domains
(D1-D4), each consisting of 6 transmembrane
Voltage-gated Na+ channels are
heteromultimeric complexes of a large, heavily
glycosylated -subunit and 1 or 2 smaller
ß-subunits.10 For heterologous expression of recombinant
Na+ channels in Xenopus oocytes, an
-subunit alone is usually sufficient to form functional channels,
whereas ß-subunits may be required for normal
gating.11 The ß1-subunit
greatly accelerates the inactivation of brain and skeletal muscle
Na+ channels expressed in Xenopus
oocytes. The ß1-subunit also shifts the voltage
dependence of steady-state inactivation toward more negative potentials
and accelerates recovery from inactivation. It is plausible to infer
that the ß1-subunit may modify the functions of
T1620M mutant channels if the mutation is located within or adjacent to
the structures required for -/ß1-subunit
association.
In this study, we characterize the functional roles of the auxiliary
ß1-subunit underlying the pathogenesis of the
Brugada syndrome. The heterologously expressed T1620M channel did not
show persistent current, in contrast to LQT3 mutant channels; however,
it exhibited a shift of voltage dependence of steady-state inactivation
toward more positive potentials. Coexpression of a human
ß1-subunit (hß1)
further shifted the midpoint of steady-state inactivation
(V1/2) and substantially accelerated recovery
from inactivation, possibly by destabilizing the inactivation state.
Because the activation kinetics of T1620M were near normal, coexpressed
hß1 exposed a more severe functional defect
that resulted in a greater overlap in the relationship between channel
inactivation and activation (window current) in T1620M. Because the
ß1-subunit is expressed in the
heart,12 13 14 we propose that these biophysical mechanisms
ascribed to aberrant association between
-/ß1-subunits underlie the pathogenesis of
the Brugada syndrome.
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Methods |
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Construction of T1620M Mutant Channel cDNA
Amino acid substitution of methionine for Thr1620 (T1620M) of hH1 was performed by an overlap extension polymerase chain reaction (PCR) strategy with 4 oligonucleotide primers: hH1-4418F (5'-TCAACCAACAGAAAAAGT-3'), T1620M-R (5'-GGAAGA-GCATCGGGGAGAAGAA-3'), T1620M-F (5'-CTCCCCGA-TGCTCTTCCGAGT-3'), and hH1-5006R (5'-GCCAAAGATG-GAGTAGATGA-3'), as previously described.9 A 608-bp PCR product was digested with BstEII/BamHI and subcloned back into wild-type hH1 (WT) to assemble the T1620M-hH1 construct. Multiple independent clones were isolated, and their sequence was verified by dideoxynucleotide sequencing of the final constructs.
Heterologous Expression and Electrophysiology
The cDNAs encoding WT, T1620M-hH1 (T1620M), and
hß113 were transcribed in vitro from
pSP64T constructs by use of SP6 RNA polymerase, and the resultant sense
cRNAs were microinjected into Xenopus oocytes and then
incubated at room temperature in ND-96 solution (96 mmol/L NaCl,
2 mmol/L KCl, 1.8 mmol/L CaCl2, 1
mmol/L MgCl2, 5 mmol/L HEPES [pH 7.5]) for
1 to 4 days.13 In some experiments, oocytes were perfused
with ND-96 solution with 30 µmol/L tetrodotoxin (TTX; Sigma) to
block Na+ currents and allow determination of
TTX-sensitive current component.8 Whole-cell currents were
recorded from oocytes with the 2-microelectrode voltage clamp, as
previously described.13
Cell-attached macropatch recordings were performed in oocytes
with a patch-clamp amplifier (Axopatch 200B, Axon Instruments) based on
methods previously described.15 The patch pipettes had tip
resistances of 0.4 to 1.0 M
and were filled with ND-96 solution.
Recordings were performed with a bath solution predicted to be
isopotential and isomolar with the intracellular oocyte milieu
and containing 9.6 mmol/L NaCl, 88 mmol/L KCl, 11 mmol/L
EGTA, and 5 mmol/L HEPES (pH 7.4). The leak and residual
capacitive currents were digitally subtracted online by the P/4
protocol. Patch-clamp recording with cell-attached
configuration was used because of its stability, and no significant
differences in Na+ channel kinetics were
identified between cell-attached and inside-out configurations. In some
experiments, whole-cell patch-clamp recordings were performed
with tsA201 cells transfected with either WT or T1620M plasmid in the
presence of hß1.7
To assess steady-state channel inactivation and recovery from
inactivation, standard double-pulse protocols were used. Unless
otherwise specified, the holding potential was set to -120 mV, and
Na+ currents were recorded during test
potentials to -20 mV. For assessment of steady-state inactivation, the
membrane potential was stepped to a voltage between -120 and -20 mV
for 500 ms, and then peak Na+ current was
measured during a -20 mV test potential. Recovery from inactivation
was assessed by a double-pulse protocol consisting of a 500-ms prepulse
to 20 mV, which was designed to fully inactivate all
channels, followed by a variable-duration interpulse interval
(
t) at various potentials between -80 and -120 mV and a test pulse
to -20 mV. The pulse protocol cycle time was 5 seconds unless
otherwise stated. Currents were filtered at 5 kHz (-3 dB, 4-pole
Bessel filter) and digitized by use of analog-to-digital interface
(Digidata 1200, Axon Instruments). Voltage control, data acquisition,
and analysis were accomplished by use of pClamp6 software (Axon
Instruments). All experiments were performed at 22°C.
Data Analysis
The time course of inactivation was fit with a biexponential
function:
I(t)/Imax=A
+Afxexp(-t/
f)+Asxexp(-t/s),
where A is a constant value,
Af and As are fractions of
fast and slow inactivating components, and f
and s are the time constants of fast and slow
inactivating components, respectively. Conductance curves were computed
by use of the equation
G=I/(Vm-Erev), where G is
conductance, I represents the peak test-pulse current,
Vm is the test pulse potential, and
Erev is the measured reversal potential.
Steady-state inactivation and conductance-voltage relationship were fit
with the Boltzmann equation
I/Imax={1+exp[(V-V1/2)/k]}-1
to determine the membrane potential for half-maximal activation
(V1/2) and the slope factor k. We
analyzed recovery from inactivation by fitting data using a
nonlinear least squares minimization method with a
monoexponential equation:
I(t)/Imax=Axexp(-t/)+C, where t is the
recovery time interval and is the time constant of recovery,
respectively.
Results were presented as mean±SE. Statistical comparisons were made with the unpaired Student’s t test to evaluate the significance of the difference between means. Statistical significance was assumed for P<0.05.
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Results |
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Onset of Inactivation
Figure 2
shows
representative current traces from oocyte macropatches
expressing either WT or T1620M in the absence or presence of
coexpressed hß1. Neither channel allele
exhibited persistent currents, the
electrophysiological characteristic
commonly observed for LQT3 mutations. Furthermore, no detectable
TTX-sensitive late Na+ currents were observed in
channels of WT, WT+hß1, T1620M, or
T1620M+hß1 (data not shown). Macroscopic
current decays of WT and T1620M in the absence or presence of
hß1 were fit with a biexponential function.
Time constants of the rapidly inactivating component
(f) and slowly inactivating component
(s) of WT, WT+hß1,
T1620M, and T1620M+hß1 were indistinguishable
at all test potentials between -55 and 20 mV (Figure 3A). The fractions of each component were
also comparable (data not shown). These data suggest that the onset of
inactivation was virtually identical between WT and T1620M and was not
affected by the ß1-subunit.
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Activation, Steady-State Inactivation, and Window Current
Activation kinetics were measured by oocyte cell-attached
macropatch techniques. Peak current-voltage relationships (Figure 3B
) and peak conductance-voltage relationships (Figure 3C) of WT, WT+hß1, T1620M, and
T1620M+hß1 were nearly superimposable. There
were no significant differences in the values of membrane voltage of
the midpoint (V1/2) and the slope factor (k) for
activation among these channels (Figure 3C;
Table). These data suggest that
the activation kinetics of T1620M were comparable to those of WT, and
the ß1-subunit did not alter the activation
kinetics of either channel.
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Steady-state inactivation was measured by 2-electrode voltage-clamp
technique, because this technique usually provides stable
recordings and does not exhibit any time-dependent changes in
channel inactivation kinetics, which are often observed in patch-clamp
recordings.16 The V1/2 and
slope factor of steady-state inactivation of WT were -69.2±0.8 mV and
4.2±0.1, respectively, and were not altered by the coexpression of
hß1 (Figure 4A;
Table), consistent with our previous
findings.13 The V1/2 of T1620M was
significantly (
5 mV) shifted toward more positive potentials
(-64.4±1.0 mV) compared with WT in the absence of
hß1, with no change in the slope factors
(Figure 4B). Coexpression of hß1
significantly shifted the V1/2 of T1620M further
toward more positive potentials (-60.0±0.8 mV, P<0.001),
whereas the slope factors were not altered. Therefore, coexpression of
hß1 shifted the voltage dependence of
steady-state inactivation of T1620M overall 10 mV toward more
positive potentials compared with WT without changing the voltage
dependence. Because activation kinetics were normal in T1620M and were
not affected by the ß1-subunit, coexpression of
the ß1-subunit exposed a more severe functional
defect that resulted in greater overlap in the relationship between
channel inactivation and activation window current in T1620M (Figure 4B). We also observed a similar shift in the voltage dependence
of steady-state inactivation for the mutant toward more positive
potentials using whole-cell patch clamp of channels expressed in tsA201
cells (WT+hß1, V1/2=
-91.2±0.9 mV, n=7; T1620M+hß1,
V1/2= -87.5±1.2 mV, n=12;
P<0.05).
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Recovery From Inactivation
Recovery from inactivation was assessed by a double-pulse protocol
with various recovery potentials by use of the 2-electrode voltage
clamp. At a recovery potential of -120 mV, the time courses of
recovery from inactivation of WT, WT+hß1, and
T1620M were nearly superimposable (Figure 5A), consistent with our previous
observations that the ß1-subunit does not
affect recovery from inactivation of the cardiac -subunit
isoform.13 17 Recovery from inactivation of
T1620M+hß1 seemed to be faster than
WT+hß1 at -120 mV; however, the differences
were not statistically significant (Figure 5A). At a recovery
potential of -80 mV, hß1 remarkably
accelerated recovery from inactivation of the T1620M channel (Figure 5B). T1620M without hß1 also showed a
tendency to recover from inactivation faster than WT or
WT+hß1; however, no statistically significant
differences were observed between them. The time course of recovery
from inactivation at each recovery potential was fit with a
single-exponential equation, and the time constants were plotted
against the recovery potential (Figure 5C). Coexpressed
hß1 did not alter recovery from inactivation of
WT, but it significantly accelerated that of T1620M, and its effects
were marked at recovery potentials more positive than -100 mV.
Consequently, coexpression of hß1 rendered the
recovery process of T1620M less voltage dependent. Recovery from
inactivation at -80 mV was 3 times faster in
T1620M+hß1 than in
WT+hß1 (WT+hß1,
=31.9±3.8 ms, n=6; T1620M+hß1,
=10.5±0.9 ms, n=12; P<0.001). Increased rate and
decreased voltage dependence of recovery from inactivation suggest that
the inactivated state of the T1620M mutant channel is
destabilized by the ß1-subunit.
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Discussion |
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The present study demonstrates the electrophysiological properties of a cardiac Na+ channel mutation of the Brugada syndrome (T1620M). The basic properties of the recombinant T1620M mutant channel expressed in Xenopus oocytes that were shown in a previous study5 were (1) a shift of voltage dependence of steady-state inactivation toward more positive potentials and (2) 20% to 30% accelerated recovery from inactivation. Channel dysfunction of T1620M became obvious when oocytes were coinjected with the mutant channel R1232W, which turned out to be a rare polymorphism identified along with T1620M in the affected members of a Brugada syndrome family.5 However, the biophysical properties of T1620M itself seem to be rather subtle and do not fully explain the severe clinical phenotype or ECG findings of Brugada syndrome patients.2 18 In the present study, we demonstrate that the Na+ channel mutation T1620M exhibits not only intrinsic channel dysfunction but also more profound inactivation defects resulting from coexpression of the ß1-subunit. The voltage dependence of steady-state inactivation is further shifted toward more positive potentials (an overall shift of 10 mV compared with WT+ß1; Figure 3
), and the recovery from
inactivation is markedly accelerated (3 times faster in
T1620M+ß1 at a recovery potential of -80 mV
compared with WT+ß1; Figure 5). Thus,
the ß1-subunit destabilizes the inactivation
state of the T1620M mutant channel. Furthermore, because the activation
kinetics of T1620M are normal regardless of the presence of the
ß1-subunit (Figures 3B and 3C),
the positive shift of the steady-state inactivation curve results in
greater overlap in the relationships of channel activation and
inactivation (Figure 4B). The occurrence of the window current
and the destabilized inactivation state will induce hyperexcitability
and an arrhythmogenic substrate in Brugada syndrome patients.
Comparison With Congenital LQT Syndrome (LQT3)
The Brugada syndrome and LQT3 are allelic disorders that result
from defects in SCN5A. The mutated residue Thr1620 of the
Brugada syndrome is located at D4/S3-S4, which is in close vicinity to
Arg1623, the residue responsible for the de novo LQT3 mutation R1623Q
located at the outermost positively charged residue of D4/S4 (Figure 1).9 Site-directed mutagenesis and functional
studies of naturally occurring Na+ channel
mutations have revealed that D4/S3-S419 and the
neighboring outermost positively charged residue of D4/S4 are
implicated in activation-inactivation coupling.9 20
Despite the adjacency of the residues Thr1620 and Arg1623 of hH1, the
clinical manifestations of the Brugada syndrome (T1620M) and LQT3
(R1623Q) and the biophysical properties of their mutant channels are
distinct. The R1623Q patient exhibits a prolonged QT interval on ECG
and recurrent episodes of ventricular arrhythmia
(torsade de pointes) soon after birth. This malignant clinical
phenotype correlates well with the biophysical characteristics.
Recombinant R1623Q channels show unusually slow macroscopic
inactivation along with persistent Na+ currents
due to prolonged channel opening time and channel bursting
behavior.9 In contrast, T1620M Brugada syndrome patients
do not exhibit QT prolongation on ECG. The recombinant T1620M channel
does not show late current or slow macroscopic inactivation. These data
confirm that the Brugada syndrome and LQT3 are distinct entities from
both a clinical and a biophysical standpoint.
Pathophysiological Implications
On the basis of these findings, it is concluded that the
ß1-subunit and the mutant -subunit play
significant roles in the pathophysiology of the Brugada syndrome. The
ß1-subunit is a small auxiliary protein with a
single transmembrane domain. It is widely expressed in excitable cells,
such as in brain, nerve, heart, and skeletal muscle, and is encoded by
a single gene.13 It has been demonstrated that the
recombinant ß1-subunit modulates the expression
levels and gating kinetics of brain11 and skeletal
muscle13 Na+ channels in oocytes.
When expressed alone, these isoforms exhibit anomalously slow
macroscopic inactivation, slow recovery from inactivation, and a
positively shifted steady-state inactivation curve. Coexpression of the
ß1-subunit shifts the voltage dependence of
steady-state inactivation curves toward more negative potentials and
restores normal gating properties of channels observed in native
tissues. In contrast to its dramatic effects on brain and skeletal
muscle Na+ channel function, the
ß1-subunit has little or no effect on the
gating of cloned cardiac Na+
channels.13 21
Structure-function relationships of the
-ß1 interaction have not been elucidated;
however, studies with site-directed mutagenesis22 23 and
Na+ channel–specific toxins19 24
have provide substantial information. It is believed that - and
ß1-subunits associate in the proximity of the
-scorpion binding sites25 and that the overlapping
region consisting of extracellular portions of D1/S5-S6, D4/S5-S6, and
D4/S3-S4 plays an important role in determining the
ß1-subunit–induced gating modulation. The
mutation T1620M on D4/S3-S4 may alter the physical association between
the - and ß1-subunits of the
Na+ channel, presumably because the residue
Thr1620 of the -subunit could reside within the
ß1-subunit binding domain. Alternatively, it is
possible that the ß1-subunit interacts
elsewhere on the -subunit, but these structures are coupled
allosterically to gating.
Clinical Implications
This study using coexpression of the
ß1-subunit clearly demonstrates that the
functional abnormalities associated with T1620M are likely to be more
severe in vivo than has been shown in oocytes expressing T1620M alone.
The expression of both normal and mutated channels in the heart of a
patient with Brugada syndrome would promote
heterogeneity of the refractory period in
myocardium, which in turn serves as an ideal substrate for
the development of reentrant arrhythmia.26
Nevertheless, the functional abnormalities of T1620M identified in the
present study do not seem be sufficient to explain all the clinical
manifestations observed in the Brugada syndrome. The ECG pattern of the
Brugada syndrome has been attributed to the transmural
heterogeneity of repolarization of the right
ventricular outflow tract. Because the magnitude and
duration of the Na+ current during phase 0 of the
cardiac action potential determines the voltage at which phase 1
begins, it is speculated that perturbations in
Na+ currents could have an effect on the kinetics
of the transient outward K+ current
(Ito), which is predominantly expressed in
epicardial cells.27 Furthermore, the ECG
abnormalities of patients with Brugada syndrome transiently normalize
during follow-up and subsequently return to the typical
pattern,18 and they are modulated by the autonomic
balance and administration of class Ia or Ic antiarrhythmic
drugs,28 which suggests significant roles of the autonomic
nervous system in the pathogenesis of the Brugada syndrome. It is not
clear whether the mutant channel T1620M (or
T1620M+hß1) is more susceptible to autonomic
nervous system modulations or antiarrhythmic drugs than WT. It is
possible that there are additional unidentified Brugada syndrome
mutations within SCN5A; alternatively, the Brugada syndrome
might be a heterogeneous disorder involving multiple
responsible genes, as is the case with congenital LQT. The genes
encoding Ito may be the potential
candidates. These hypotheses require further investigation.
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Acknowledgments |
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This work was supported in part by a grant-in-aid for exploratory research, Japan Society of the Promotion of Science (11877008), and the National Institute of Health (NS32387). Dr George is an Established Investigator of the American Heart Association. We thank Drs Christoph Fahlke, Jong-Kook Lee, Noritsugu Tohse, and Masayuki Sakurai for useful discussions.
Received May 20, 1999; revision received July 21, 1999; accepted August 4, 1999.
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