© 2000 American Heart Association, Inc.
UltraRapid Communication |
Enhanced Na+ Channel Intermediate Inactivation in Brugada Syndrome
From the Departments of Pharmacology (D.W.W., J.R.B., A.L.G.), Anesthesiology (J.R.B.), and Medicine (A.L.G.), Vanderbilt University School of Medicine, Nashville, Tenn, and the Department of Cardiovascular Medicine (N.M., A.K.), Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Correspondence to Alfred L. George, Jr, Division of Genetic Medicine, 451 MRB-II, Vanderbilt University Medical Center, Nashville, TN 37232-6304. E-mail al.george{at}vanderbilt.edu
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Abstract |
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Abstract—Brugada syndrome is an inherited cardiac disease that causes sudden death related to idiopathic ventricular fibrillation in a structurally normal heart. The disease is characterized by ST-segment elevation in the right precordial ECG leads and is frequently accompanied by an apparent right bundle-branch block. The biophysical properties of the SCN5A mutation T1620M associated with Brugada syndrome were examined for defects in intermediate inactivation (IM), a gating process in Na+ channels with kinetic features intermediate between fast and slow inactivation. Cultured mammalian cells expressing T1620M Na+ channels in the presence of the human ß1 subunit exhibit enhanced intermediate inactivation at both 22°C and 32°C compared with wild-type recombinant human heart Na+ channels (WT-hH1). Our findings support the hypothesis that Brugada syndrome is caused, in part, by functionally reduced Na+ current in the myocardium due to an increased proportion of Na+ channels that enter the IM state. This phenomenon may contribute significantly to arrhythmogenesis in patients with Brugada syndrome. The full text of this article is available at http://www.circresaha.org.
Key Words: Brugada syndrome • Na+ channel • SCN5A • slow inactivation
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Introduction |
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Sudden cardiac death due to ventricular arrhythmias continues to be a common cause of death in industrialized nations. Recent advances have elucidated the molecular genetic basis of several forms of the congenital long-QT syndrome and the more recently defined Brugada syndrome. Disease-producing mutations have been identified in several cardiac ion channel genes including SCN5A, which encodes the voltage-gated Na+ channel
subunit.1 2
Understanding the pathogenesis of these uncommon familial syndromes
will provide a foundation of knowledge that will help unravel the
complex pathophysiology of more common cardiac arrhythmia
syndromes. Brugada syndrome is a form of idiopathic ventricular fibrillation that exhibits a characteristic ECG pattern consisting of ST elevation in the right precordial leads and an apparent right bundle-branch block.3 Inheritance appears to be autosomal dominant, and there is often a family history of unexplained sudden death. On mechanistic grounds, several cardiac ion channels were identified as potential candidate genes for Brugada syndrome. In 1998, Chen et al2 reported the discovery of mutations in SCN5A in families with Brugada syndrome. Subsequently, additional SCN5A mutations have been identified, and many laboratories have contributed to the functional characterization of these alleles using heterologously expressed recombinant Na+ channels.4 5 6 7
A prevailing concept regarding the pathophysiology of Brugada syndrome is that heterogeneity of repolarization exists across the right ventricular wall, in part due to asymmetric transmural expression of the transient outward current, Ito.8 Theoretical arguments and experimental data support the notion that a reduction in Na+ current will further amplify the transmural voltage gradient during repolarization and greatly increase the propensity for reentrant arrhythmia.9 Some SCN5A mutations associated with Brugada syndrome, especially mutations associated with aberrant exon splicing or a frameshift, are quite consistent with this pathophysiological concept. In contrast, some missense mutations in SCN5A yield functional channels with subtle biophysical defects.
Studies of recombinant, heterologously expressed Na+ channels have been valuable for elucidating biophysical defects in mutant Na+ channels that may be mechanistically compatible with the Brugada phenotype. The most well-studied missense mutation is a substitution of theronine 1620 by methionine (T1620M). In the initial report of this mutation, Chen et al2 demonstrated subtle changes in the voltage dependence of steady-state inactivation and enhanced recovery from fast inactivation when the recombinant Na+ channel mutant was expressed in Xenopus oocytes. These gating defects were surprisingly inconsistent with a loss of function phenotype.10 11 More recently, Dumaine et al12 have emphasized the importance of conducting electrophysiological recordings at more physiological temperatures using cultured mammalian cells to define the precise biophysical defect in this mutant allele. This study demonstrated that at near physiological temperatures, T1620M Na+ channels exhibit more rapid fast inactivation kinetics than wild-type Na+ channels. Although this biophysical defect would explain diminished Na+ channel current density in Brugada syndrome, these studies were carried out in the absence of the ß1 subunit, which our studies suggest may be critical for full expression of the T1620M gating defect.11 Despite the apparent extensive analysis of this single missense mutation in Brugada syndrome, a clear, unifying pathophysiological mechanism related to specific biophysical defects associated with this disease has not emerged.
Recently, Veldkamp et al13 described the functional disturbances exhibited by an unusual SCN5A insertional mutation (1795insD) associated with both clinical phenotypes of congenital long-QT syndrome and Brugada syndrome. This mutation exhibits sustained Na+ current during long depolarizations compatible with many other mutations associated with congenital long-QT syndrome.14 In addition, these investigators revealed a novel molecular mechanism for Brugada syndrome whereby the mutation enhances a slow inactivation process with intermediate kinetics.13 The intermediate inactivation process in Na+ channels discussed by these authors has been defined operationally as a form of inactivation occurring with a 10- to 100-ms time constant.15 Enhanced intermediate inactivation was argued to represent an additional biophysical mechanism by which Na+ channels may have reduced function in the setting of Brugada syndrome. The question remains whether other Brugada syndrome missense mutations exhibit this novel biophysical mechanism, or whether this is unique to the 1795insD allele.
On the basis of these studies, we examined the T1620M Brugada syndrome SCN5A mutation with the intent of understanding its intermediate inactivation properties. By contrast to previous reports, when T1620M is coexpressed in cultured mammalian cells with the human ß1 subunit, the kinetics of development and recovery from fast inactivation were not significantly different from wild-type channels, even at near physiological temperature (32°C). However, entry into the intermediate inactivated state was significantly enhanced in the mutant compared with the wild type in the presence of ß1. These findings support the hypothesis that Brugada syndrome may be caused in part by an enhancement of IM that would decrease Na+ channel current density during the cardiac action potential and increase the propensity for cardiac arrhythmia in these patients.
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Materials and Methods |
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Heterologous Expression of Na+ Channels in tsA201 Cells
Cells (tsA201) were transiently transfected with pRcCMV-hH1 or pRcCMV-T1620M using SuperFect (Qiagen Inc) in combination with a bicistronic plasmid16 (pGFP-IRES-hß1) encoding green fluorescent protein (GFP) and the human ß1 subunit (hß1). Transfections used 1 µg of channel-encoding plasmid DNA and 1 µg of pGFP-IRES-hß1. In some experiments, pGFP-IRES without hß1 was cotransfected with pRcCMV-hH1 or pRcCMV-T1620M. Cells expressing GFP were selected for patch-clamp recording experiments. Transiently transfected cells were transferred to a heating chamber (Warner Instrument Corp) for electrophysiological measurements 40 to 72 hours after transient transfection.
Electrophysiology
Na+ currents were recorded using the
whole-cell patch-clamp technique as described
previously.17 18 Electrode resistance ranged from 0.8 to
1.5 M
. Data acquisition was carried out using an Axopatch 200B
patch-clamp amplifier and pCLAMP v8.0 software (Axon Instruments, Inc).
Currents were filtered at 5 kHz (-3 dB, four-pole Bessel filter) and
digitized using an analog-to-digital interface (Digidata 1200B,
Axon Instruments). Capacitance and series resistance were adjusted
(70% to 85%) to obtain minimal contribution of the capacitive
transients. The holding potential was -120 or -90 mV for all
experiments, and details of each pulse protocol are given schematically
in the figures and explained in the Results section.
The bath solution contained (in mmol/L) NaCl 145, KCl 4, CaCl2 1.8, MgCl2 1, HEPES 10, and glucose 10, pH 7.35 (adjusted with NaOH). The pipette solution (intracellular solution) contained (in mmol/L) NaF 10, CsF 110, CsCl 20, EGTA 10, and HEPES 10, pH 7.35 (adjusted with CsOH). In some experiments at 32°C, the following intracellular solution was used (in mmol/L): NaCl 35, CsF 105, EGTA 10, and HEPES 10, pH 7.35 (adjusted with CsOH). Osmolarity was adjusted to 310 mOsm with sucrose for all solutions.
Data Analysis
All data were analyzed by using pCLAMP v8.0 (Axon
Instruments, Inc), and the figures were prepared by using SigmaPlot
v2000 (SPSS Inc). The time course of inactivation of macroscopic
current was fit with a two-exponential function:
I(t)/Imax=A1xexp(-t/
1)+A2xexp(-t/2).
Steady-state availability was 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.
Recovery from inactivation was analyzed by fitting data to two
exponentials:
I(t)/Imax=Afx[1-exp(-t/f)]+Asx[1-exp(-t/s)].
All data were fit using a nonlinear least-squares minimization
method.
Results are presented as mean±SE, and the statistical comparisons were made using the unpaired Student’s t test. Statistical significance was assumed for P<0.05.
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Results |
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Characterization of T1620M Fast Inactivation
Initially, we examined the kinetics and steady-state voltage dependence of fast inactivation in cultured mammalian cells (tsA201) expressing either wild-type recombinant human heart Na+ channels (WT-hH1) or T1620M channels at near physiological temperature (32°C) in the absence and presence of hß1. To facilitate voltage control at 32°C, we transfected cells with a minimal amount of plasmid DNA to achieve low-amplitude Na+ currents, used lower-resistance patch pipettes (0.8 to 1.0 M
), and
tested cells of smaller size that tend to exhibit smaller currents and
smaller capacitance transients. Data were collected only from cells
that had peak current amplitudes of 1 to 3 nA. Current rundown was not
observed at room temperature where Na+ currents
stabilize within 5 to 10 minutes after rupturing the cell membrane. By
contrast at 32°C, current amplitude is less stable and may run down
with variable rate and extent. We carefully monitored
time-dependent changes in peak current amplitudes and selected data for
statistical analysis from cells exhibiting <5% rundown over
the time course of the experiment. To minimize the contribution of
time-dependent shifts of channel availability,18 all data
were collected within 20 minutes after establishing the whole-cell
patch clamp.
Figure 1
shows the voltage dependence and
the rate of decay of Na+ currents recorded at
32°C from cells expressing either WT-hH1 or T1620M in either the
presence or absence of hß1. In all cases, cells
were held at a negative membrane potential (-120 mV) to remove
inactivation, and then test pulses of -80 to +50 mV in 10-mV
increments were applied. At 32°C, the current activation,
inactivation, and current-voltage relationships were similar between
WT-hH1 and T1620M. No significant difference was observed between the
time course or voltage dependence of fast inactivation for WT-hH1 and
T1620M in the absence or presence of hß1. These
data are in contrast with that reported by Dumaine et
al,12 who observed that an increased rate of fast
inactivation occurred at warm temperature. Potential causes for these
differences are discussed below.
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We tested the rate of Na+ channel recovery from
fast inactivation at 32°C using a conventional two-pulse protocol
(Figure 2A). We used a 20-ms conditioning
pulse of -10 mV to engage fast, but not slow or intermediate,
inactivation, followed by a variable recovery interval and a
-10-mV test pulse. In the presence of hß1,
both WT-hH1 and T1620M channels exhibit similar kinetics and voltage
dependence of recovery from fast inactivation. Most channels (>95%)
recovered rapidly with time constants <2 ms, and there were no
significant differences between WT-hH1 and T1620M. To examine the
voltage-dependent loss of channel availability due to fast
inactivation, we used a 10-ms prepulse of varying potentials from -160
to -10 mV followed by a -10-mV test pulse. In the presence of
hß1, cells expressing T1620M exhibit a midpoint
(V1/2) of channel availability that is shifted 6
mV toward more positive potentials compared with WT-hH1
(WT-hH1+hß1: -72.5±1.3 mV, n=9;
T1620M+hß1: -66.3±0.9 mV, n=13;
P<0.01). This result is consistent with previously
reported findings examining T1620M in Xenopus
oocytes,2 or mammalian cells11 12
although Baroudi et al19 did not observe this shift in
tsA201 cells using voltage-clamp protocols similar to those we
used.
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Characterization of Intermediate Inactivation
(IM)
Na+ channels exhibit multiple types of
inactivation that can be distinguished by their time course. Fast
inactivation occurs over a few milliseconds and is the classical type
of inactivation gating described originally by Hodgkin and
Huxley.20 Slow inactivation is a distinct gating process
that occurs over a time period of a few hundred milliseconds to tens of
seconds and is important physiologically for
determining the number of channels available for firing action
potentials.21 One form of slow inactivation that has drawn
attention recently has intermediate kinetics and has been designated as
IM.15 Because during
cardiac action potentials the myocyte membrane is depolarized for
periods sufficient to elicit IM, we
examined the impact of the T1620M mutation on
IM to address the question whether this
could be a factor in the pathogenesis of Brugada syndrome.
Initial experiments were designed to characterize the development of
IM at room temperature (22°C) using a
two-pulse protocol illustrated in Figure 3A (inset) that includes an initial
conditioning prepulse to -10 mV (P1), followed by a 20-ms step to
-120 mV to remove fast inactivation, and a final test pulse (P2) to
-10 mV to assess channel availability. With progressively longer
prepulse durations, Na+ current diminished more
in cells coexpressing T1620M and hß1 than those
transfected with WT-hH1 and hß1. This effect
became marked as prepulse durations exceeded 200 ms, consistent
with IM kinetics.13 15 At
a prepulse duration of 1000 ms, 5.4±1% of WT-hH1 current was
inactivated compared with 16.3±2% for T1620M
(P<0.01). Interestingly, no difference in the development
of inactivation with this pulse protocol was observed between T1620M
and WT-hH1 in the absence of hß1 (for P1=1000
ms, 27±1% WT-hH1 current was inactivated, n=6, versus
29±3% for T1620M, n=7).
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Additional experiments were performed to characterize differences
in recovery and steady-state voltage dependence of
IM between WT-hH1 and T1620M. Figure 4A illustrates differences in the
kinetics of recovery from inactivation induced by a 1000-ms
depolarization to -10 mV for WT-hH1 and T1620M, both coexpressed with
hß1. Analysis of these data reveal two
kinetic components reflected in the time constants
1 (WT-hH1+hß1:
3.5±0.4 ms, n=11; T1620M+hß1: 6.3±0.7 ms,
n=13, P<0.05) and 2
(WT-hH1+hß1: 73.1±10.3 ms;
T1620M+hß1: 88.1±9.5 ms; NS). Notably,
the time constant that best reflects recovery from intermediate
inactivation (2) is not changed by the
mutation. The faster component of recovery from inactivation, reflected
in the 1 value, predominates in both channels
and is slower in the mutant (1 probably
represents a mixture of fast and intermediate inactivation in
this experiment). More importantly, there is a significant difference
in the partitioning between the two kinetic components exhibited by
T1620M such that a much greater proportion of mutant channels recovers
with the slower time constant (WT-hH1+hß1:
2 amplitude=7.4±0.9%, versus
T1620M+hß1: 2
amplitude=26.1±2.5%, P<0.001). We interpret this as
evidence that T1620M channels more readily enter the intermediate
inactivated state during the 1000-ms conditioning pulse
than WT-hH1. Once inactivated, both WT-hH1 and T1620M
channels recover from the intermediate inactivated state at
similar rates.
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Figure 4B
illustrates the steady-state partitioning of WT-hH1
and T1620M channels into inactivated states over a wide
range of membrane potentials. After a 1000-ms depolarization to induce
intermediate inactivation, cells were briefly hyperpolarized (20 ms) to
allow recovery from fast inactivation before channel availability was
measured (see Figure 4B inset). In the presence of
hß1, the availability of mutant channels over a
wide range of depolarized voltages was substantially lower than WT-hH1,
consistent with enhanced partitioning of channels into the
intermediate inactivated state.
Intermediate Inactivation at 32°C
The data presented above are consistent with
enhanced entry of T1620M channels coexpressed with
hß1 into the intermediate
inactivated state. The duration of the human cardiac action
potential provides an appropriate time frame during which a significant
degree of intermediate inactivation could develop. Therefore, the
significant differences observed between WT-hH1 and T1620M could result
in lower steady-state Na+ channel availability
and reduced depolarizing myocardial Na+ current
in the mutant, consistent with prevailing concepts concerning
the pathophysiology of Brugada syndrome. To test whether this
observation could be relevant to the in vivo situation, we repeated the
experiment illustrated in Figure 3B at near
physiological temperature (32°C). Figure 5 demonstrates a similar enhancement of
IM at this warmer temperature in cells
expressing T1620M with hß1. After a 1000-ms
depolarization to -10 mV and a brief repolarizing step to -120 mV to
allow recovery from fast inactivation, the proportional decrement in
channel availability was 
2-fold greater for T1620M than WT-hH1
(WT-hH1+hß1: 14.1±2.2%, n=5; versus
T1620M+hß1: 27.7±2.8%, n=13,
P<0.01). To illustrate the potential
physiological significance of this effect, we
recorded peak Na+ currents at 32°C during a
series of 500-ms test depolarizations to +10 mV at a rate simulating a
cardiac cycle length of 0.52 seconds (115 bpm). Data shown in Figure 6 demonstrate that T1620M channels
exhibit a significantly greater degree of activity-dependent loss of
availability. Overall, our results support the conclusion that the
Brugada syndrome Na+ channel mutation T1620M
exhibits enhanced development of intermediate inactivation, and this
biophysical defect could be a significant factor in the pathogenesis of
this disease.
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Discussion |
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Brugada syndrome is a rare but highly informative condition of susceptibility to potentially lethal ventricular tachyarrhythmias that provides an important model for understanding the pathomechanism underlying more common arrhythmia syndromes.22 23 Perhaps the most attractive and well-substantiated hypothesis to explain the cellular basis of Brugada syndrome involves reduced myocardial Na+ current and the resultant imbalance of inward and outward currents particularly in the right ventricular epicardium where disproportionate expression of the transient outward current creates a transmural voltage gradient and dispersion of repolarization.8 24 This hypothesis has been validated by experimental animal models and by computational methods.9 12 The theory helps to explain the characteristic ECG pattern observed in patients with Brugada syndrome, provides a basis for understanding the effects of Na+-channel blocking agents to aggravate this phenotype, and may illustrate mechanisms underlying acquired ventricular arrhythmia syndromes such as acute myocardial infarction.
Previous work to characterize the molecular genetics and molecular physiology of Brugada syndrome has provided evidence that reduced myocardial Na+ current results from disease-associated mutations in SCN5A. Two of the first reported Brugada syndrome mutations severely disrupt the coding potential of the SCN5A mRNA and are expected to result in nonfunctional Na+ channels.2 Other missense mutations in SCN5A have been described and a few have been characterized using recombinant Na+ channels expressed heterologously in cultured cells. At least one mutant allele (R1432G) is nonfunctional,7 but other mutations do not prevent expression of functional Na+ channels. The first identified missense mutation T1620M, which we have re-studied here, has been evaluated by several laboratories, and variable defects in fast gating properties have been described.2 11 12 19 These defects include shifts in the steady-state voltage dependence of fast inactivation and activation as well as changes in the rate of recovery from fast inactivation or entry into the fast inactivated state. These findings are in contrast to those characterizing prototypic LQT3 SCN5A mutations in which there is an almost universally observed defect in fast inactivation manifest as a small noninactivating current component during long depolarizations. The variable results reported by laboratories studying T1620M may be attributable to several factors. It is clear that subtle phenotypic differences in the character of fast inactivation may stem from the nature of the heterologous cells used (Xenopus oocytes versus culture cells),19 the presence or absence of the ß1 subunit,11 temperature,12 and subtle differences in voltage-clamp protocols and recording solutions.
In the present study, we selected cultured mammalian cells as the
heterologous model and performed experiments predominantly in the
presence of hß1, which is known to be expressed
in heart25 and likely interacts with the cardiac
Na+ channel subunit.26 We also
examined fast gating behavior of the mutant channel at near
physiological temperature based on the report of
Dumaine et al.12 Our results suggests that a small but
significant shift in the voltage dependence of steady-state fast
inactivation occurs in cells expressing T1620M, but we find less
evidence for a substantial effect of the mutations on fast
inactivation. There are two possible explanations for differences
between our data and those reported by Dumaine et al.12
Our experiments used a lower intracellular Na+
concentration (10 versus 35 mmol/L), and our values for the time
constants of fast inactivation for WT-hH1 are smaller than those
reported in the other study.12 Unfortunately, it is
not possible to precisely reconcile these differences between our study
and previous work performed on T1620M. However, there is little doubt
that defects in fast gating can theoretically contribute to the
pathophysiology of reduced Na+ current associated
with Brugada syndrome. As demonstrated by the work of Dumaine et
al,12 subtle changes in the kinetics of fast inactivation
are predicted to exert a substantial effect on the morphology of
epicardial action potentials as deduced from computer modeling
experiments. These findings are clearly in line with the prevailing
hypothesis of Brugada syndrome and further validation of these results
will be important.
In addition to defects in fast gating, we examined whether concomitant alterations in inactivation processes occurring with a slower time course might contribute to the biophysical dysfunction of T1620M channels. This work was motivated by the recent observations of Veldkamp et al13 describing an unusual SCN5A mutation associated with the clinical phenotypes of both long-QT and Brugada syndromes. This unusual mutation (1795insD) exhibits the sustained noninactivating current characteristic of prototypic LQT3 mutations as well as a previously undescribed enhancement of intermediate inactivation. This enhancement of intermediate inactivation is consistent with reduced steady-state Na+ current and is compatible with the Brugada syndrome hypothesis described above. Our experiments similarly demonstrate enhanced development of intermediate inactivation in the T1620M allele associated with the Brugada syndrome phenotype alone. Thus, our work demonstrates that an enhancement in a slow gating process may underlie the biophysical defect in Na+ channel mutations associated with Brugada syndrome.
Intermediate inactivation and other slow gating states exhibited by Na+ channels may be important determinants of the action of local anesthetic and antiarrhythmic agents in heart15 and may participate in the pathogenesis of inherited skeletal muscle Na+ channelopathies. In particular, mutations in the SCN4A Na+ channel associated with hyperkalemic periodic paralysis exhibit defects in both fast and slow gating.27 28 In this case, impairment of slow inactivation may contribute to the ability of depolarized muscle fibers to have sustained attacks of inexcitability and paralysis.29
The structural basis for slow gating in Na+ channels may relate to several regions of the channel protein including the pore-forming segments. The T1620M allele is located in an extracellular loop between the S3 and S4 segments of domain 4 in the cardiac Na+ channel and therefore is not intimately associated with structures known to contribute to permeation. At this point, it is unclear whether this residue participates directly or indirectly in mediating intermediate inactivation or other slow gating processes. However, recent data indicate a role for the adjacent domain 4, S4 segment in slow inactivation.30
In summary, we have described enhanced intermediate inactivation in a missense SCN5A mutation associated with the Brugada syndrome. This biophysical property of mutant Na+ channels may contribute to the overall pathogenesis of the disease by reducing steady-state myocardial Na+ current. These observations provide another perspective for understanding the molecular basis of ventricular arrhythmia syndromes and may help provide an additional functional target for drugs to treat these disorders.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (NS32387 to A.L.G., GM56307 to J.R.B.) and the American Heart Association. A.L.G. and J.R.B. are Established Investigators of the American Heart Association. We thank David Johns (Institute for Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md) for providing the GFP-IRES vector.
Received September 13, 2000; accepted September 13, 2000.
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