(Circulation. 2000;102:921.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome
From the Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (H.A., X.H.T.W., R.S.K.), and the Heiden Department of Cardiology, Bikur Cholim Hospital (J.B.), and Department of Genetics, Hebrew University (B.K.), Jerusalem, Israel. The first 2 authors contributed equally to this work.
Correspondence to R.S. Kass, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, New York, NY 10032. E-mail rsk20{at}columbia.edu
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Abstract |
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Background—Multiple mutations of SCN5A, the gene that encodes the human Na+ channel
-subunit, are linked to 1 form of the congenital long-QT
syndrome (LQT-3). D1790G (DG), an LQT-3 mutation of the C-terminal
region of the Na+ channel -subunit, alters steady-state
inactivation of expressed channels but does not promote sustained
Na+ channel activity. Recently, flecainide, but not
lidocaine, has been found to correct the disease phenotype,
delayed ventricular repolarization, in DG
carriers. Methods and Results—To understand the molecular basis of this difference, we studied both drugs using wild-type (WT) and mutant Na+ channels expressed in HEK 293 cells. The DG mutation conferred a higher sensitivity to lidocaine (EC50, WT=894 and DG=205 µmol/L) but not flecainide tonic block in a concentration range that is not clinically relevant. In contrast, in a concentration range that is therapeutically relevant, DG channels are blocked selectively by flecainide (EC50, WT=11.0 and DG=1.7 µmol/L), but not lidocaine (EC50, WT=318.0 and DG=176 µmol/L) during repetitive stimulation.
Conclusions—These results (1) demonstrate that the DG mutation
confers a unique pharmacological response on expressed channels; (2)
suggest that flecainide use–dependent block of DG channels underlies
its therapeutic effects in carriers of this gene mutation; and (3)
suggest a role of the Na+ channel -subunit C-terminus in
the flecainide/channel interaction.
Key Words: sodium • ion channels • antiarrhythmia agents • pharmacology • electrophysiology • genes
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Introduction |
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The congenital long-QT syndrome is an inherited cardiac disorder defined by prolonged ventricular repolarization, recurrent syncope, a propensity to polymorphous ventricular tachycardia (torsades de pointes), and sudden death.1 2 Molecular genetic studies have identified defects in the
-subunit of the cardiac voltage-gated ion
channel (SCN5A) that are linked to 1 form of the disease:
LQT-3.3 Initial functional analysis of most
SCN5A mutations has revealed mutant
Na+ channels that fail to inactivate
completely on prolonged depolarization,4 5 6 7 8 a
property sufficient to delay repolarization of the
ventricular action potential and increase vulnerability of
the heart to arrhythmias.9 In contrast, the D1790G
(DG) SCN5A mutation,10 located in the
cytoplasmic region of the -subunit C-terminus, causes a marked
negative shift in the relationship between channel availability and
membrane potential and alters inactivation kinetics of mutant
channels11 but does not promote sustained inward
current.7 Pharmacological analysis of LQT-3 mutant channels expressed heterologously has provided evidence that sodium channel blockers that interact with either the inactivated or open state of the channel12 13 effectively block maintained current conducted by mutant channels,14 15 16 17 18 19 20 shorten action potential duration in cellular studies,21 22 and in preliminary studies correct QT prolongation in patients.22 23
Because the biophysical properties of the DG mutation do not promote maintained current during the action potential plateau phase, it had been suggested that agents such as lidocaine would not be effective in correcting the disease phenotype linked to this mutation.7 Clinical studies24 have confirmed this prediction but, in addition, have shown that flecainide, which preferentially blocks open but not inactivated channels,25 is effective in correcting DG-induced QT prolongation in patients carrying the DG gene defect. However, the mechanism underlying this mutation-specific therapeutic efficacy has not yet been determined.
Here, we report the pharmacological profile of DG channels expressed in a mammalian cell line and show that this point mutation confers a flecainide sensitivity that is distinct from wild type (WT) and at least 1 other LQT-3 mutant channel.20 Our results reveal marked drug-specific differences in channel modulation that are consistent with the clinical efficacy of both lidocaine and flecainide and suggest that over concentration ranges that are used clinically, it is the marked difference in flecainide’s use-dependent block (UDB) of DG compared with WT channels that underlies its therapeutic efficacy. The results of this study provide further support for the approach of mutation-specific pharmacology as a basis for the management of inherited cardiac arrhythmias.
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Methods |
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Expression of Recombinant Na+ Channels
HEK 293 cells (Cold Spring Harbor Laboratories) were grown under culture conditions and transfected with equal amounts of Na+ channel
- (WT or DG, respectively),
hß1-, and/or
hß2-subunit cDNAs subcloned individually into
the pcDNA3 (Invitrogen) vector (total cDNA, 2.5 µg) by a lipofection
procedure previously described by us.7 Control experiments
(data not shown) indicated no significant differences in channel
activity with or without drug for these subunit combinations.
ß-Subunit cDNAs were gifts of Drs L. Isom (University of Michigan,
hß2) and A. George (Vanderbilt University,
hß1), and the DG mutation was constructed as
previously described.7
Electrophysiology
Membrane currents were measured by whole-cell patch-clamp
procedures26 with Axopatch 200B amplifiers (Axon
Instruments) and the following solutions (mmol/L): internal: CsCl 60,
aspartic acid 50, CaCl2 1,
MgCl2 1.2, HEPES 10, EGTA 11, and
Na2ATP 5; pH corrected to 7.2 with CsOH;
external: NaCl 130, CsCl 5, CaCl2 2,
MgCl2 1.2, HEPES 10, and glucose 5; pH corrected
to 7.4 with CsOH. Drug (Sigma Chemical Co) solutions were made from
10 mmol/L (flecainide) or 100 mmol/L (lidocaine) stock
solutions in H2O. Experiments were carried out
with pClamp7 software (Axon Instruments), and data were
analyzed with Origin software (Microcal Software). Unless
otherwise specified in the figure legends, experiments were carried out
at room temperature (22°C). Measurements at higher temperature were
performed with a solution heater (In-line Heater SH-27B, Warner
Instrument Corp) warming the superfusate to 37°C.
Recordings were made during 25-ms test pulses to -10 mV from
-100-mV holding potentials. Tonic block (TB) was measured at 0.033 Hz
after steady state was achieved in the presence of drug (1 minute for
lidocaine and 2 to 4 minutes for flecainide). Steady-state inactivation
was measured with 5-second conditioning pulses followed by a test pulse
(-10 mV), with an interpulse interval of 30 seconds. Steady-state UDB
was reached in response to trains of variable numbers of pulses
(100 to 600, -10 mV) at frequencies indicated in the figure legends.
UDB was measured as block induced by pulse trains relative to TB for a
given drug concentration. UDB data were normalized to currents
recorded with the same protocols but in the absence of
drug.
Data are represented as mean±SEM. Two-tailed Student’s t test was used to compare means; a value of P<0.05 was considered statistically significant.
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Results |
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TB of WT and Mutant Channels
Because the DG mutation alters the voltage-dependence of steady-state inactivation of expressed channels,7 we first tested for differences between the interactions of lidocaine and flecainide with the inactivated state of WT and DG channels. Figure 1
shows that lidocaine,
but not flecainide, induces marked hyperpolarizing shifts in the
steady-state inactivation relationship for both WT and DG channels.
Furthermore, the effects of lidocaine on inactivation are approximately
the same for WT and DG channels.
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The lidocaine selective shift in inactivation predicts greater TB of DG
versus WT channels by lidocaine, but not flecainide, at
physiologically relevant holding potentials.
This prediction is confirmed in the experiments summarized in Figure 2. However, at clinically relevant
concentrations27 of lidocaine (
30 µmol/L) and
flecainide (3 µmol/L), neither drug discriminates between WT
and DG channels on the basis of TB.
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) channels by lidocaine (C) and flecainide
(D). Graph shows peak current after drug application, normalized to
peak current in absence of drug, plotted as a function of drug
concentration. Smooth lines are according to
1/(1+[drug]/EC50)n. EC50 for
lidocaine is 894 (WT) and 205 (DG); EC50 for flecainide is
59.3 (WT) and 48.2 (DG); n=3 to 6 cells per condition.
UDB: Distinctions Between WT and DG Channels
Therefore, we next compared block that accumulates with repetitive
activity when DG mutant and WT channels are exposed to lidocaine and
flecainide (Figure 3). Again at
clinically relevant concentrations (30 µmol/L), there is no
difference between lidocaine block of WT and DG channels (Figure 3A). In contrast, there is a statistically significant
(P<0.001) difference between flecainide UDB of DG and WT
channels at the clinically relevant concentration of 3 µmol/L.
This difference is evident over a broad concentration range:
EC50 for flecainide UDB of DG channels is roughly
5 times lower than for block of WT channels (Figure 3B). In
contrast, UDBs of WT or DG channels by lidocaine are approximately the
same over all concentrations tested. In addition, the distinction in
use-dependent drug action between WT and DG channels is retained when
the frequency range of pulse application is extended to a broader
frequency range (Figure 3C and 3D).
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Effect of DG Mutation on Recovery From Flecainide Block
Block that accumulates as a consequence of repetitive channel
activity (UDB) is caused by a balance between the time course of the
onset of block (during depolarization) and the recovery from block
(during repolarization).12 13 To understand the marked
sensitivity of DG channels to UDB, we next investigated the time course
of the recovery from UDB. Here, we focused only on the effects of
flecainide, because there was little difference between WT and DG
channels in response to UDB by lidocaine (Figure 3A
and 3C).
In these experiments, we applied a "conditioning" train of pulses
for a fixed duration and frequency to induce flecainide block of
channels. As illustrated in Figure 4, in
the absence of drug, DG channels tend to recover faster from
inactivation that occurs as a consequence of the conditioning train. In
the presence of flecainide, repriming of channels is very different:
now DG channels recover very slowly. Even after 10 seconds at the
holding potential (-100 mV) under pulse-free conditions, only a small
fraction of the flecainide-blocked current recovers. This result
suggests that the flecainide-bound DG channel is very stable and that
infrequent pulsing can still be very effective at accumulating block
because once blocked, channels remain nonconducting for tens of
seconds.
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Clinical Efficacy of Flecainide: Distinctions Between UDB of WT and
DG Channels
The dramatic slowing of flecainide unblock caused by the DG
mutation (Figure 4) has important implications for the clinical
usefulness of this compound in the treatment of LQT-3 in carriers of
the DG mutation. Because use-dependent flecainide block discriminates
between WT and DG mutant channels (Figure 3), it is important to
demonstrate UDB of DG channels under conditions that more closely
resemble those encountered in the heart. Thus, we tested for
differences between WT and DG channels in the response to flecainide,
when longer pulses (400 ms), which mimic the duration of action
potentials in LQT-3 patients, are applied at a
physiological frequency (1 Hz) and temperature
(37°C). These experiments (Figure 5)
confirm that, even under these conditions, the extremely slow recovery
from flecainide block of DG channels is sufficient to cause
significantly greater block of DG versus WT channels.
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Discussion |
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Molecular Basis for Mutation-Specific Pharmacology: Implications for a Role of C-Terminus in Inactivation and Drug Activity
The principal finding of this study is that a LQT-3–linked mutation of the heart
-subunit of the Na+
channel dramatically and specifically changes the manner by which
channels encoded by the mutant gene interact with sodium
channel–blocking drugs. The mutation confers a higher sensitivity to
UDB by flecainide, but not lidocaine, over a clinically relevant
concentration range. Flecainide TB is not affected by the DG mutation.
Our findings thus illustrate the importance of investigating
mutation-induced changes not only in channel function but also in
channel pharmacology. Voltage-dependent block of Na+ channel currents by antiarrhythmic drugs is a consequence of distinct interactions with different states of the voltage-gated Na+ channel. Lidocaine and flecainide differ in their modes of action in that lidocaine interacts preferentially with inactivated channels, and drug block is not necessarily dependent on channel openings,25 28 whereas flecainide requires channels to open and is not dependent on channels entering the inactivated state to promote block.25 29
We observed that the DG mutation does not influence the interaction of
lidocaine with the Na+ channel, even if TB was
greater than for mutant channels (Figure 2). Indeed, this effect
is explained by the fact that lidocaine shifts the steady-state
inactivation curve by the same amount for WT as for the DG mutant
channel, but the DG mutation by itself already shifts this curve
by 
-20 mV in the absence of drug. Because flecainide has a
much weaker effect on the inactivation curve (Figure 1), there
is little difference between flecainide-induced TB of WT and DG
channels. In contrast, the DG mutation markedly increases flecainide
UDB of channels, in large part because of the pronounced slowing of the
repriming of DG channels in the presence of the drug (Figure 4).
This specific alteration of the sensitivity to UDB by flecainide is not
a general property of all LQT-3 mutant channels. Recently, Nagatomo et
al20 found that LQT-3 
KPQ mutant channels have an
intrinsically higher affinity than WT channels to flecainide, but in
the case of this mutation, sensitivity to both TB and UDB is increased.
Thus, our data indicate that the DG point mutation causes a unique
pharmacological response of the expressed channels, which is distinct
not only from WT but also from KPQ mutant channels.
The DG mutation is a nonconservative change from an aspartic acid to a
glycine only 18 amino acids away from transmembrane segment S6 in the
C-terminus of the Na+ channel -subunit, a
region of the channel not previously considered to play a major role in
the molecular interactions of flecainide.30 Our data
clearly show that this is not the case and raise the possibility that
other residues of the C-terminus may also be important in determining
pharmacological responses of Na+ channels.
Importantly, 1 other nonconservative C-terminus LQT-3 mutation (E1784K)
has been reported recently,6 and a C-terminus insertion
mutation (1795insD) has been linked to both Brugada’s syndrome and
LQT-3.31 Our work strongly suggests that these mutations
may also modify the interactions of the encoded channels by flecainide
(and probably other drugs), raising the possibility of pharmacological
targeting of a broad range of mutation-induced phenotypes. As
has been shown for KPQ and DG channels, however, determination of
the pharmacological profile must be carried out systematically on a
mutation-by-mutation basis before this would be possible.
Relationship Between Molecular Pharmacology and Therapeutic
Efficacy
Our data on recombinant human Na+ channels
complement those of Benhorin et al,24 which have shown
that flecainide, but not lidocaine, significantly decreased the QTc
interval in DG carriers by 10% but was without effect in control
patients. This difference was even more striking when the effect of
flecainide on the marked repolarization heterogeneity
seen in DG carriers was considered. Our experiments indicate that over
the clinically relevant drug concentration range and under
physiological conditions, flecainide discriminates
between WT and DG primarily because of the pronounced effect of the DG
mutation on flecainide UDB. The correlation between the clinical
results and our data strongly suggests that it is this mechanism of
action that underlies the therapeutic usefulness of flecainide compared
with lidocaine in the treatment of carriers of the DG mutation.
Interestingly, flecainide has also recently been shown to be very
effective in treating carriers of the KPQ LQT-3 mutation (A.J.
Moss, personal communication), even though, as discussed above,
the interactions of flecainide with KPQ and DG mutant channels
differ. In the case of both channel defects, however, recovery from the
drug-blocked state is markedly slowed compared with WT channels, and it
may be this common mode of action that makes this drug so useful as a
therapeutic tool in the treatment of carriers of these gene
defects.
In summary, we have found that the LQT-3 DG mutation changes the pharmacological response of encoded channels in a manner that differs not only from WT but also from other LQT-3 mutant channels. The pharmacological profile of DG channels shows distinct changes that occur over a therapeutically relevant concentration range. Our data provide further support for the usefulness of a mutation-specific pharmacological approach for the management of distinct inherited ion channel defects.
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Acknowledgments |
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This work was supported by US Public Health Service grant R01-HL-568105–02 (Dr Kass). Dr Abriel was supported by the Swiss National Foundation for Fellowships in Medicine and Biology and Mr Wehrens by the Dutch foundation De Drie Lichten.
Received February 14, 2000; revision received March 17, 2000; accepted March 24, 2000.
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