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Cardiovascular Research 2002 53(2):348-354; doi:10.1016/S0008-6363(01)00494-1
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Copyright © 2001, European Society of Cardiology

A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease

Nobumasa Shiraia, Naomasa Makitaa,*, Koji Sasakia, Hisataka Yokoia, Ichiro Sakumaa, Harumizu Sakuradab, Jun Akaic, Akinori Kimurac, Masayasu Hiraokad and Akira Kitabatakea

aDepartment of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-8638, Japan
bDepartment of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan
cEtiology and Pathogenesis Research Unit, and Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
dEtiology and Pathogenesis Research Unit, and Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

* Corresponding author. Tel.: +81-11-716-1161; fax: +81-11-706-7874 makitan{at}med.hokudai.ac.jp

accepted 19 September 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Loss of Na+ channel function has been implicated in idiopathic ventricular fibrillation (IVF) and Brugada syndrome. We have studied the biophysical properties of an IVF mutation (S1710L) that exhibited an unusual clinical phenotype: rate-dependent bundle branch block without manifestation of Brugada-type ECG pattern. Methods: The mutant S1710L channels were expressed in mammalian cells and their gating properties, studied using whole-cell patch clamp techniques, were compared with wild-type (WT) and a Brugada syndrome mutant channel T1620M. Results: The S1710L channel exhibited significantly faster macroscopic current decay than WT or T1620M. In addition, S1710L showed a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation than in WT or T1620M. In addition to the alterations in fast inactivation most commonly observed in Brugada syndrome mutations, S1710L exhibited marked enhancement in slow inactivation and a large positive shift of activation that potentially decreases conduction velocity. Conclusions: These functional abnormalities may be responsible for the overlapping clinical phenotypes associated with Brugada syndrome and the cardiac conduction defect, a novel cardiac Na+ channelopathy.

KEYWORDS Arrhythmia (mechanisms); Conduction (block); Na-channel; Sudden death; Ventricular arrhythmias


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Voltage-gated Na+ channels are membrane proteins responsible for the initial phase of the action potential in most excitable cells. They normally open briefly upon depolarization, and then rapidly inactivate by a mechanism referred to as ‘fast inactivation’, thereby contributing to the initiation and conduction of the action potentials. With repetitive and prolonged depolarization, Na+ channels enter more stable non-conducting states by a distinct mechanism called ‘slow inactivation’ [1]. Slow inactivation has various life times ranging from hundreds of milliseconds to many seconds. Genetic defects in fast and/or slow inactivation of the human skeletal muscle Na+ channel result in hereditary skeletal muscle disorders such as hyperkalemic periodic paralysis [2] and paramyotonia congenita [3].

Idiopathic ventricular fibrillation (IVF) is a primary electrical disorder predisposing individuals to sudden cardiac death without obvious structural heart diseases [4]. A subgroup of IVF characterized by the ECG findings of right bundle branch block and ST elevation in the right precordial leads is called Brugada syndrome [5]. Several mutations responsible for Brugada syndrome have been identified in the human cardiac sodium channel {alpha} subunit gene (SCN5A) [6]. Heterologously expressed Brugada syndrome mutant Na+ channels exhibit various functional defects in activation and fast inactivation, most of which promote reduced Na+ current density (loss-of-function) [7]. Since K+ channels encoding transient outward K+ current (Ito) counterbalancing Na+ current are predominantly expressed in the right ventricular epicardium, diminished Na+ channel current results in greater transmural voltage-gradient in the right ventricle, leading to ST elevation in V1–3 characteristic of Brugada syndrome [8].

In addition to IVF/Brugada syndrome, mutations of SCN5A have also been demonstrated in one form of congenital long QT syndrome (LQT3) [9] and an inherited cardiac conduction defect [10,11], constituting ‘cardiac Na+ channelopathies’. Molecular basis of LQT3 is the persistent late Na+ current due to the defects in fast inactivation (gain-of-function), that prolongs the repolarization phase of the cardiac action potential. Little is known about the biophysical defect responsible for the inherited cardiac conduction defect, but alterations in the activation gating have been attributed to the cardiac conduction delay in an isolated cardiac conduction defect family with an SCN5A mutation (G514C) [11]. Clinical phenotypes and channel properties demonstrated for these three syndromes are distinct and appear to be mutually exclusive. However, a recent study has revealed that there is significant clinical overlap among these disorders [12]. A family with an SCN5A mutation 1795insD showed a phenotype combining QT prolongation and ST elevation [13]. Moreover, provocation by the sodium channel blocker flecainide induces ST elevation in some LQT3 patients, providing additional evidence of the overlap between LQT3 and Brugada syndrome [14].

We have recently reported a case of IVF who has a novel SCN5A mutation (S1710L) located within the S5–S6 loop (P-loop) of domain 4 [15]. Heterologously expressed S1710L channels in mammalian cells exhibit severe abnormalities in activation and fast inactivation gating properties, all of which potentially result in greater reduction in Na+ channel availability during excitation than other Brugada syndrome mutations reported so far. Despite severe biophysical abnormalities, the patient did not exhibit the typical Brugada syndrome clinical phenotype (i.e. no ST elevation in V1–3) but developed right bundle branch block during tachycardia, suggesting distinct mechanisms underlying these clinical manifestations.

In this study, we analyzed the biophysical properties of two mutant Na+ channels associated with either Brugada syndrome (T1620M) or IVF (S1710L), and found that the S1710L channel shows markedly enhanced slow inactivation similar to the mutant channel 1795insD, and a large positive shift of the voltage-dependence of activation in S1710L resembling the inherited cardiac conduction defect mutation, G154C. These biophysical properties may underlie the unusual clinical phenotypes and biophysical properties of S1710L and suggest another Na+ channelopathy with overlapping characteristics of Brugada syndrome and the inherited cardiac conduction defect.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Mutant Na+ channel cDNAs encoding T1620M and S1710L were made as previously described [15,16] and subcloned into pRcCMV (Invitrogen). The human kidney cell line tsA-201 was transiently transfected with either wild-type (WT) or mutant plasmid in combination with a plasmid encoding CD8 to visually identify transfected cells using Dynabeads (M-450 CD8 Dynal). Whole-cell patch clamp recordings were carried out at room temperature based on the methods previously described [15,16] with some modification. After rupturing the membrane, the cells were dialyzed for 10 min before starting data acquisition. The holding potential for all pulse protocols was –150 mV unless otherwise stated. The bath solution contained 145 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2, 10 mM Hepes, and 10 mM glucose, pH 7.35 (NaOH). The pipette solution contained 10 mM NaF, 110 mM CsF, 20 mM CsCl, 10 mM EGTA, and 10 mM Hepes, pH 7.35 (CsOH). Voltage-clamp command pulses were generated using pCLAMP6 (Axon Instruments) and currents were filtered at 5 kHz (–3 dB, 4-pole Bessel filter). The auxiliary β1 subunit increases the current density 2- to 3-fold sometimes beyond the range of voltage control, which may require reduced extracellular Na+ concentrations. Since extracellular Na+ concentrations significantly modify the kinetics of slow inactivation [17], we did not co-express β1 subunit or modify Na+ concentrations in the present study.

The data were analyzed using Clampfit (Axon Instruments), SigmaPlot (SPSS Science) and StatView (SAS Institute Inc.). Results are presented as means±standard error and statistical comparisons were made using analysis of variance (ANOVA) with Dunnett post-hoc test to evaluate the significance of the difference between means. Statistical significance was assumed for P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Macroscopic Na+ current
As shown in Fig. 1A, macroscopic current decay of WT and T1620M were nearly superimposable, and the time constants and the fractions analyzed by two-exponential fitting were comparable between WT and T1620M. By contrast, S1710L showed significantly accelerated current decay. Time constant of fast fraction was significantly smaller for S1710L at almost all the test potentials examined (Fig. 1B and C). Overall, the onset of fast inactivation was significantly accelerated in S1710L compared with WT or T1620M. Current–voltage relationship of peak current was shifted towards the positive direction for both T1620M and S1710L (Fig. 1D). Persistent Na+ current, channel properties most commonly observed in LQT3 mutant Na+ channels, was not evident in either channels.


Figure 1
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  		Fig. 1 (A) Whole-cell recording of WT, T1620M and S1710L channels expressed in tsA-201 cells. Currents were recorded from a holding potential of –150 mV and stepped from –90 to +90 mV for 20 ms in 10 mV increments. (B, C) Macroscopic current decay was fit with a two-exponential function: I(t)/Imax=A{infty}+Afxexp(–t/{tau}f)+Asxexp(–t/{tau}s), where Imax is the peak current, t is time, A8 is a constant value, Af and As are fractions of fast and slow components, and tf and ts are the time constants of fast and slow components, respectively. Statistical significance in the difference between WT and mutant is shown (* P<0.05, ** P<0.01). (D) Current–voltage relationships normalized to the maximum peak Na+ current.

 
3.2 Activation and fast inactivation
Voltage-dependence of activation of T1620M was significantly shifted towards more positive potentials (+6.8 mV relative to WT) and that of S1710L was further shifted in the same direction by 18.7 mV (Fig. 2A). A positive shift of the activation curve will increase the voltage difference between the resting membrane potential (Vrest) and the activation threshold leading to decreased conduction velocity, which has been proposed as a mechanism responsible for the conduction delay observed in an isolated cardiac conduction defect case associated with a novel SCN5A mutation [11]. Slope factor of T1620M was comparable with WT, however it was significantly larger in S1710L (Table 1), showing that the voltage-dependence of activation was significantly attenuated in S1710L.


Figure 2
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  		Fig. 2 (A) Voltage-dependence of peak conductance and steady-state fast inactivation. The conductance was estimated by 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. Normalized peak conductance was plotted as a function of membrane potential. To assess steady-state fast inactivation, the peak currents were measured during a –20 mV test potential after a series of 100 ms prepulses from –170 to –30 mV. Normalized peak current was plotted as a function of prepulse potential. Steady-state activation curves and steady-state fast inactivation curves were fit with the Boltzmann equation: y=[1+exp((V–V1/2)/k)]–1, where y is the activation or fast inactivation variable, V is the membrane potential, V1/2 is the midpoint of the curve, and k is the slope factor. (B) Recovery from fast inactivation. Recovery from fast inactivation was assessed by a double pulse protocol as shown in the inset. Fractional recovery was determined as the ratio of peak currents measured at –20 mV after a given test interval ({Delta}t) to the maximum peak current. The recovery time courses were best fit by a two-exponential function: I(t)/Imax=C–Afxexp(–t/{tau}f)–Asxexp(–t/{tau}s), where t is the recovery time interval, Af and As are fractions of fast and slow components, and {tau}f and {tau}s are the time constants of fast and slow components of recovery, respectively.

 

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  		Table 1 Gating parameters of WT and mutant hH1 channels

 
The voltage-dependence of fast inactivation elicited by 100 ms prepulse was significantly shifted towards more positive direction by 13.1 mV for T1620M, and negative direction by 21.7 mV for S1710L (Fig. 2A, Table 1). Slope factors of fast inactivation curves were comparable for all three channels (Table 1). Recovery from fast inactivation of T1620M elicited by 500 ms prepulse was nearly identical to WT, however, S1710L showed significantly delayed recovery kinetics (Fig. 2B). Time constant of the rapidly recovering component ({tau}f) was significantly larger in S1710L than WT (Table 1), while there were no differences in the fractions of fast and slow components among the three channels.

3.3 Closed-state inactivation
Depolarization with membrane potentials below the activation threshold does not usually change the gating kinetics of most channels, however, a population of channels enters an inactivated state without channel opening by a mechanism called ‘closed-state inactivation’. Closed state inactivation greatly affects the availability of the channels at voltages near the resting membrane potentials, thereby controlling the Na+ current amplitude of the action potential. As shown in Fig. 3, the time course of the development of closed-state inactivation at –100 mV was significantly facilitated in S1710L (WT: 114±12 ms, n=7, S1710L: 33±7 ms, n=8, P<0.01), but not in T1620M (90±12 ms, n=7). These data suggest that a substantial fraction of S1710L channels are inactivated at voltages near at the resting potential, while a smaller fraction is inactivated from closed states in T1620M. Channel availability after the 100 ms prepulse shown by the closed-state inactivation protocol should correspond to the data point at –100 mV of the steady-state inactivation curve. Channel availability at 100 ms of each channel was; WT: 0.67±0.07, T1620M: 0.85±0.03, S1710L: 0.22±0.06 (P<0.01 vs. WT), and have good agreement with the channel availability at –100 mV obtained from the steady-state inactivation curves; WT: 0.64±0.07, T1620M: 0.90±0.02, S1710L: 0.12±0.03. Therefore, these voltage shifts of steady-state inactivation are the indigenous gating properties of the mutant channels but not due to time-dependent voltage drift often observed in patch clamp experiments [18].


Figure 3
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  		Fig. 3 Closed-state inactivation. From a holding potential of –150 mV, cells were prepulsed to –100 mV for various durations and then stepped to –20 mV to determine the availability of INa during the prepulse. Time course for development of closed-state inactivation were fit with a monoexponential equation: I/Imax=Axexp(–t/{tau})+C, where {tau} is the time constant and A is the fraction of closed-state inactivated channels. Time course of closed-state inactivation is significantly facilitated in S1710L but not in T1620M.

 
3.4 Slow inactivation
With sustained depolarization, Na+ channels enter ‘slow inactivation’, a gating mode distinct from fast inactivation. The time course of the development of slow inactivation was fit well with a single-exponential function (Fig. 4A). The time constant of the development of slow inactivation ({tau}) was comparable among the three channels, however, the fraction of the channels capable of entering slow-inactivated state was significantly larger in S1710L as compared with WT or T1620M (Table 1). These data show that the onset of slow inactivation is significantly enhanced in S1710L.


Figure 4
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  		Fig. 4 (A) Development of slow inactivation. Cells were depolarized with a prepulse at 0 mV with various durations to elicit slow inactivation, followed by a 100 ms interpulse at –150 mV to allow recovery from fast inactivation. The remaining Na+ currents were measured at a test pulse to 0 mV. The data from development of slow inactivation were fit with a monoexponential equation: I/Imax=Axexp(–t/t)+C, where t is the time constant and A is the fraction of slow inactivated channels. (B) Recovery from slow inactivation. To assess recovery from slow inactivation, the voltage was stepped to 20 mV for 60 s, and then to –150 mV. The extent of recovery was measured by applying repetitive test pulses of 5 ms to –20 mV followed by a step back to –150 mV at a frequency of 1 Hz which allows complete recovery of the channels from fast inactivation. Recovery from slow inactivation was fit with a two-exponential equation.

 
Recovery from slow inactivation was evaluated by applying a long depolarizing pulse (+20 mV, 60 s) followed by a short repolarization (–150 mV, 100 ms) to allow recovery from fast inactivation (Fig. 4B). Subsequently, the time course of recovery from slow inactivation was evaluated by a train of brief depolarizations (5 ms), and was analyzed by two-exponential curve fitting. Similar to the onset of slow inactivation, the time constants of both rapidly and slowly recovering component from slow inactivation were comparable, however, the fractions of both components were significantly larger in S1710L (Table 1).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
LQT3, IVF/Brugada syndrome and the inherited cardiac conduction defect are defined as cardiac Na+ channelopathies displaying distinct clinical phenotypes and the biophysical properties depending upon the location of the mutations [7,12]. The molecular mechanism responsible for LQT3 is persistent Na+ current during the action potential repolarization due to defects of Na+ channel fast inactivation (gain-of-function) that delay cellular repolarization and prolong the QT interval [9]. Molecular basis of Brugada syndrome is believed to be diminished myocardial Na+ current (loss-of-function) and a resultant increase in transmural voltage gradient and ST elevation on ECG [12]. The functional consequence of diminished Na+ current is more prominent in epicardial cells because the transient outward K+ current (Ito) that counterbalances Na+ current is predominantly expressed in epicardial cells. Little has been known about the precise pathophysiology underlying inherited cardiac conduction defect [10], however, positive shift of voltage-dependence of activation has recently been implicated in a mutant Na+ channel of an isolated conduction disease [11].

Substantial evidence has shown that there is significant overlap among cardiac Na+ channelopathies [14]. Patients with the C-terminal SCN5A mutation 1795insD manifested clinical features of both LQT3 and Brugada syndrome [13]: QT prolongation at slow heart rates, and distinctive ST elevations occurred with exercises. Heterologously expressed 1795insD mutant channels exhibit biophysical abnormalities of both LQT3 (sustained late Na+ current) and Brugada syndrome (augmented intermediate kinetic component of slow inactivation; IM). Enhanced slow inactivation is also regarded as a crucial determinant of ‘rate-dependent ST elevation’, an unusual clinical phenotype that is not usually observed in LQT3 or Brugada syndrome. Based on these findings, 1795insD is regarded as an overlapping Na+ channelopathy of LQT3 and Brugada syndrome [19]. By analogy with 1795insD, we speculated that the S1710L is another overlapped Na+ channelopathy of Brugada syndrome and the inherited cardiac conduction defect, and the abnormalities in slow inactivation and activation gating may contribute to the unusual clinical outcomes, ‘rate-dependent right bundle branch block’ observed in the patient [15].

Rapid current decay, delayed recovery from inactivation, and the negative shift of voltage-dependence of steady-state inactivation comprise the fast inactivation dysfunction uniquely identified in S1710L, but not in the Brugada syndrome mutation T1620M. The S1710L channel also exhibited enhanced closed-state inactivation that was not evident in T1620M. Moreover, onset of slow inactivation is markedly enhanced and the recovery from slow inactivation is delayed. Slow inactivation is induced by repetitive and prolonged depolarization, and it substantially suppresses Na+ currents and controls excitability in nerve or skeletal muscle. Although the extent of slow inactivation is more limited in the normal cardiac Na+ channel, it potentially diminishes the availability of the S1710L mutant channel especially when the heart rate is increased [20]. All of the inactivation defects identified in S1710L, fast inactivation, closed-state inactivation and slow inactivation, strongly suggest that the S1710L channels are stabilized at the inactivated-state, which in turn results in diminishing the Na+ current in the myocardium. The Brugada syndrome mutation T1620M, on the other hand, did not show enhanced closed-state inactivation or slow inactivation under the recording conditions we used, although it exhibited enhanced intermediate inactivation (IM) when recorded in the presence of co-expressed β1 subunit at more physiological temperature [21]. Despite the severe inactivation defects, S1710L is not associated with the clinical phenotype characteristic for Brugada syndrome. Therefore, these unusual clinical phenotypes in S1710L may not be explained solely by the inactivation defects.

S1710L exhibits a large positive shift in current–voltage (I–V) relationship as is demonstrated in the inherited cardiac conduction defect mutation G514C [11]. Positively shifted I–V curve will increase the voltage difference ({Delta}V) between cardiac resting membrane potential (Vrest) and Na+ channel activation threshold. Simulation studies have demonstrated that the increase in {Delta}V in turn decreases the conduction velocity in the myocardium [11]. By analogy with tachycardia-dependent ST elevation demonstrated in 1795insD, tachycardia-dependent block observed in S1710L may be explained at least in part by the enhanced slow inactivation and positively shifted I–V relationship, and we conclude that S1710L causes another Na+ channelopathy with characteristics of both Brugada syndrome and the inherited cardiac conduction defect.

It has been widely accepted that the cytoplasmic loop connecting domains 3 and 4 (ID34) is the principal structural motif responsible for Na+ channel fast inactivation, however, the structural basis of slow inactivation is less clear. Since external pore-lining residues modulate C-type inactivation of K+ channels, it was proposed that the P-loop of each domain may play an important role in the slow inactivation of Na+ channels. Slow inactivation of cardiac Na+ channel isoform is significantly limited as compared to the skeletal muscle isoform, and the replacement of P-loops confers cardiac phenotype to the skeletal muscle isoform, suggesting that the P-loops are the responsible structures determining the slow inactivation [20]. Furthermore, mutations at the P-loops of the rat skeletal muscle Na+ channel (rSkM1), W402C (domain 1) [22] and F1236C (domain 3) [23], result in alteration of slow inactivation gating process. S1710L is the first naturally occurring P-loop mutation of the cardiac Na+ channel that modifies slow inactivation. These mutations are located adjacent to the putative filter residues that determines the ion selectivity of the Na+ channel as a ring of amino acid of each domain, so-called ‘DEKA’ (D372, E898, K1419, and A1711 of human cardiac Na+ channel sequence) [24]. Thus, it is possible to assume that the filter residues and neighboring regions in the P-loops may be crucial determinant for slow inactivation as well as ion selectivity.

The patient with the S1710L mutation did not exhibit ST elevation following oral administration of the class I antiarrhythmic drug disopyramide [15], another unusual clinical phenotype as Brugada syndrome, although flecainide challenge test has not been performed. Recent molecular pharmacological studies have shown that structural rearrangement in the P-loop is linked to slow inactivation and use-dependent action of local anesthetic drugs [23]. It has been also demonstrated that closed-state inactivation, significantly enhanced in the S1710L, greatly affects the lidocaine binding [25]. Therefore, S1710L mutant may have altered sensitivity to antiarrhythmic drugs, may explain, in part, the unusual clinical phenotypes of the IVF mutation S1710L. These studies are currently being investigated.

Time for primary review 34 days.


   Acknowledgements
 
This study was supported in part by research grants 13670685 (NM) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and 11470342 (IS) from the Ministry of Health, Labour and Welfare, Japan. We thank A.L. George for helpful discussion.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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