© 1996 American Heart Association, Inc.
Articles |
Lidocaine Block of LQT-3 Mutant Human Na+ Channels
the Department of Physiology, University of Rochester (NY) School of Medicine.
Correspondence to Robert S. Kass, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia Uni-versity, 630 W 168th St, New York, NY 10032. E-mail rsks@uhura.cc.rochester.edu.
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Abstract |
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In transiently transfected mammalian cells we have identified pharmacological consequences of a naturally occurring deletion mutation,
KPQ, of the human heart Na+ channel 
subunit that previously has been linked to one form of the long QT syndrome, an inherited heart disease. Our results show that the Class IB antiarrhythmic agent lidocaine blocks maintained inward current through and slows recovery from inactivation of KPQ-encoded Na+ channels. Block is greater for maintained than for peak current. Because incomplete inactivation of mutant Na+ channels is now thought to underlie the prolonged ventricular action potential, which is the phenotype of this disease, and we find that the KPQ mutation speeds the recovery from inactivation of drug-free mutant channels, our results provide evidence, for the first time, that clinically relevant dysfunctional properties of an ion channel can be selectively targeted on the basis of the molecular properties conferred on the channel by an inherited genetic disorder.
Key Words: long QT syndrome • molecular genetics • Na+ channel • lidocaine • congenital heart disease
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Introduction |
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The congenital long QT syndrome is predominantly an autosomal-dominant disorder that is characterized by prolongation of the ventricular action potential as well as a propensity to ventricular tachycardia (torsade de pointes) and sudden death.1 2 The disease has been linked to at least four separate loci: chromosomes 3p2l through 24, 7q35 and 36, 4q25 through 27, and 11p15.5.3 4 5 6 However, recently, two forms of long QT syndrome have been shown to result from mutations in genes that encode voltage-dependent ion channel subunits in the heart. LQT-2, previously mapped to chromosome 7, was found to be linked to the HERG gene, which encodes one component of delayed K+ current.7 8 9 10 Another form of the disease, LQT-3, was found to be linked to a specific mutation in SCN5A, a gene that encodes the
subunit of the cardiac Na+ channel.11
Voltage-gated Na+ channels are membrane-spanning proteins12 that control the movement of Na+ and underlie the spread of excitation in ventricular and atrial muscle cells and in the Purkinje fiber network throughout the heart13 but can also contribute so-called inward "window" current that can prolong action potential duration.14 In some tissues, the voltage-gated Na+ channel is a heterotrimeric protein consisting of (33-kD), ß1 (36-kD), and ß2 (33-kD) subunits,12 15 16 but only the subunit is needed for expression of recombinant channels with biophysical and pharmacological properties similar to native cardiac channels.17 18 19 The cytoplasmic linker between repeats III and IV of the Na+ channel subunit is a key structural component that contributes to channel inactivation.17 20 21 Because the SCN5A mutation linked to LQT-3 was shown to cause the deletion of three amino acids in the III-IV cytoplasmic linker of the Na+ channel subunit, it was suggested that these deletions may cause functional changes in Na+ channel inactivation responsible for the phenotypical action potential prolongation in LQT-3, and recent studies of recombinant channels expressed in Xenopus oocytes have confirmed this.22
Class IB local anesthetic agents, such as lidocaine, mexiletine, and tocainide, are drugs that interact with Na+ channels in a voltage-dependent manner to inhibit ion flow through them. Channel block depends on the state of the channel in a complex manner, being influenced by the relative number of resting, open, and/or inactivated channels and the time course of interstate transitions.23 24 25 Biophysical measurements of modulation of native Na+ channels have provided evidence that local anesthetics bind to a site that is within the channel pore but accessible only from the intracellular side of the cell.26 27 The cloning and expression of voltage-dependent Na+ channels has allowed identification of the molecular structures and sites underlying these biophysical channel properties and confirmed the intimate relationship between drug action and channel inactivation. In particular, one region of the Na+ channel protein, transmembrane segment IVS6 of the subunit, has been shown to be critical for both fast inactivation of the channel and local anesthetic binding.28 29 Thus, because LQT-3 mutations alter channel inactivation, it is likely that interactions with local anesthetic antiarrhythmic agents differ for wild-type and mutant channels. Such differences may be exploited to develop a new therapeutic approach to management of arrhythmias that are related to this LQT-3 form of the disease, based on the specific molecular pharmacology of the mutant gene product.
Herein we report the results of experiments in which we tested directly for distinct local anesthetic modulation of Na+ channels encoded by the SCN5A gene carrying the LQT-3 mutation. We transiently transfected human embryonic kidney (HEK 293) cells with cDNAs for wild-type (hH1) and LQT-3 mutant (KPQ) forms of the human heart Na+ channel subunit to test directly the hypothesis that the LQT-3 SCN5A mutation modifies expressed Na+ channel function in a manner that confers distinct modulation of mutant channels by the antiarrhythmic local anesthetic drug lidocaine. In HEK 293 cells, we find that the LQT-3 SCN5A mutation causes significant changes in the fraction of noninactivating Na+ channel current and the time course of the onset of and recovery from inactivation, resulting in significant differences in lidocaine block of hH1 compared with KPQ Na+ channels. The results of this work can thus be used, for the first time, to define therapeutic conditions in which an antiarrhythmic drug can be used to treat selectively cardiac rhythm disturbances based on functional changes induced by a specific genetic defect.
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Materials and Methods |
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Currents were recorded using whole-cell patch-clamp procedures,30 with the following: an extracellular solution consisting of (mmol/L) NaCl 132, CsCl 5, MgCl2 1.2, HEPES 10, dextrose 5, CaCl2 2 and an intracellular solution containing (mmol/L) CsCl 60, CaCl2 1, HEPES 10, MgCl2 1, EGTA 5, K2ATP 5, cesium aspartate 50. In experiments in which [Na+]o was reduced to 20 mmol/L, N-methylglucamine chloride was used as a NaCl substitute. Currents were recorded with Axopatch 200A amplifiers (Axon Instruments) interfaced to a Gateway 2000 486 PC (Gateway 2000) under software control of pClamp Version 6.02 (Axon Instruments). Leak and linear capacity currents were subtracted by P/4 procedures in all but the pulse-train experiments. Data were plotted and statistics computed with Origin software (Microcal Software). Averaged data are presented as mean±SEM. HEK 293 cells were grown in culture and transfected as previously described,31 except that 1.2 µg hH1 or
KPQ cDNA plus 1.2 µg T-antigen cDNA (each cDNA subcloned into pcDNA3 [Invitrogen]) was incubated with 20 µL lipofectamine (GIBCO), and cells were transfected in a 50-mL culture flask. hH1 and KPQ cDNA were generous gifts of Dr Mark Keating. For each experiment, after whole-cell conditions were established by rupturing the cell membrane, we allowed a dialysis period of 4 minutes before beginning the measurement of any control records. During the dialysis period, we monitored current-voltage relationships to ensure stability and consistency in recordings. After the 4-minute dialysis period, we began experiments. Control data were collected using pulse paradigms that lasted no longer than 2 minutes. In experiments measuring the effects of lidocaine, the drug was applied via a rapid solution changer, which changes the solution around the cell in <10 seconds. We then waited 2 minutes and applied the protocols in the presence of drug (an additional maximum period of 2 minutes). When possible, recovery runs were obtained 2 minutes after returning to a drug-free solution. We tested for, but did not find, shifts in the voltage dependence of activation or steady state inactivation over the time period needed to complete experiments.
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Results |
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Na+ channels encoded by hH1 and
KPQ cDNAs were readily expressed in HEK 293 cells without coexpression of other Na+ channel subunits (Fig 1
). Fig 1A shows families of current traces recorded from two cells expressing hH1 (left) and KPQ (right) recorded during 40-ms voltage steps from a -90-mV holding potential. To improve voltage control, it was necessary to reduce [Na+]o to 20 mmol/L in these experiments. Shown in the plot is the relationship between mean peak current and test voltage (I/V), determined in hH1-transfected (n=5) and KPQ-transfected (n=5) cells. Fig 1B emphasizes currents measured at the end of the 40-ms test pulses. The traces compare higher-amplification records of currents recorded at -10 mV, near the maximum of the I/V relationship in 132-mmol/L [Na+]o to resolve possible maintained Na+ channel current. In this example, the current through hH1 channels (left) completely inactivates at the end of the 40-ms test pulses, but current through KPQ channels (right) does not inactivate completely. Instead, in the case of the KPQ channels, there is a measurable maintained inward current (arrow) that is not present for hH1 channels. This is a consistent difference in the functional properties of hH1 and KPQ channels over a wide voltage range as is indicated by the plot in Fig 1B, which shows mean current at the end of 40-ms pulses from hH1 (n=9) and KPQ (n=13) cells plotted against test-pulse voltage. We measured maintained Na+ current in every cell expressing KPQ channels when experiments were carried out in 132-mmol/L [Na+]o. In 20-mmol/L [Na+]o, the maintained current, though detectable, was greatly reduced. This result in a transfected mammalian cell line confirms the data of Bennett et al22 obtained in Xenopus oocytes at one voltage, and extends this finding to the entire voltage range of channel activation.
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The KPQ mutation changes the kinetics of both the onset of and recovery from inactivation of expressed channels. The change in the onset of inactivation kinetics is illustrated in Fig 2. Fig 2A shows examples of hH1 and KPQ current records recorded in 132-mmol/L (upper row) and 20-mmol/L (lower row) [Na+]o. We found that the time course of the onset of inactivation of wild-type (hH1) channels was best fit by a function consisting of two exponential components plus a baseline. Shown in the figure are normalized currents recorded in response to 40-ms pulses to -10 mV from a -90-mV holding potential, and superimposed on each current trace is the best-fit exponential function for each case. The onset of inactivation is faster for mutant channel activity recorded in both normal and low [Na+]o. In the case of mutant channels, records were equally well fit by functions of only a single exponential component plus a baseline (shown superimposed on KPQ current traces). The mutation reduces the contribution of the slower time constant that characterizes the onset of inactivation of wild-type channels at -10 mV. Fig 2B shows that this is the case over the range of voltages studied. The current recordings shown in Fig 2B compare the time course of the onset of inactivation of currents measured at -20 mV, -10 mV, and +10 mV. In each case, current through KPQ channels (
) inactivates faster than current through wild-type hH1 channels (
). The current records shown in Fig 2B were recorded in 20-mmol/L [Na+]o to ensure adequate voltage control, but similar results were found for currents recorded in 132-mmol/L [Na+]o. The graphs summarize the time constants obtained from the best fits to the experimental data collected in both 20-mmol/L and 132-mmol/L [Na+]o. The data indicate that the principal difference in the kinetics of the onset of inactivation caused by the KPQ mutation is caused by the absence of a detectable slow time constant.
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1 (
and 
], n=4; 
and 
], n=9; 
], n=9). Peak currents have been normalized to unity. Calibration, 2 ms.
Fig 3 illustrates the effects of the KPQ mutation on the time course of recovery from Na+ channel inactivation in the absence and presence of the Class IB antiarrhythmic drug lidocaine. In these experiments, channels were inactivated by imposition of a 100-ms conditioning pulse to -10 mV (P1), and the membrane was returned to -90 mV for a variable time period (t) before applying a second test pulse to -10 mV (P2) to assay recovery from inactivation of Na+ channel current. After a 3-second pulse-free period at -90 mV, this double-pulse paradigm was repeated with a different interpulse interval. The time course of recovery from inactivation was determined by plotting the ratio of P2 current to P1 current as a function of the interpulse interval, t, and fitting the resulting trajectories with exponential functions. Shown in the lower portions of Fig 3A and 3B are mean values of the P2(t)/P1 ratio in the absence and presence of lidocaine (100 µmol/L) for hH1 (3A) and KPQ (3B) channels. Data for mutant and wild-type channels both in the absence and presence of lidocaine were well fit by functions of two exponential components. The best-fit functions are plotted in the figure as smooth curves, and the parameters of the fits are provided in the figure caption. In the absence of drug, KPQ channels recover from inactivation faster than hH1 channels. Recovery of current after the conditioning depolarization is slowed by the addition of lidocaine, consistent with depolarization enhancement of the number of drug-bound channels, which subsequently unblock slowly at -90 mV. Lidocaine slows the recovery of both KPQ and hH1 channels, but KPQ channel recovery is still faster than hH1 channels. The difference in kinetics of recovery from lidocaine block suggests that frequency-dependent effects of the drug may differ for hH1 and KPQ channels.
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Fig 4 illustrates experiments in which we tested for differences, not only in frequency-dependent but also tonic lidocaine block of hH1 and KPQ channels. Fig 4A shows use-dependent block by lidocaine. In these experiments, cells were held at -90 mV without pulsing for 30 seconds. Then trains of 30 brief (15-ms) pulses to -10 mV were applied at different pulse frequencies from the -90-mV holding potential. Frequency-dependent block was assayed by measuring the ratio of the last (P30) to the first (P1) test pulse as a function of pulse frequency. The current traces in Fig 4A show representative use-dependent effects of lidocaine (100 µmol/L) for hH1 (left) and KPQ (right) channels at a pulse frequency of 10 Hz. There is a 70% pulse-dependent reduction in hH1 channel current, and a 54% pulse-induced reduction in KPQ channel current. As summarized in the bar graph in Fig 4A, although a consistent trend at each frequency studied, the difference in pulse-dependent block of hH1 and KPQ is not statistically significant and is not likely to be a mechanism to target mutant channels with a pharmacological approach. However, we found that tonic lidocaine block, which occurs during infrequent pulsing and develops at the resting or holding potential, does preferentially target current through mutant channels.
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We analyzed tonic block of currents elicited by 40-ms pulses to -10 mV applied at 0.1 Hz to ensure full recovery from inactivation and pulse-induced block (Fig 3
) during the interpulse interval. In addition, we analyzed current in response to 100-ms pulses (P1) applied at 0.33 Hz in the experiments of Fig 4. The results we obtained were the same for both experimental paradigms. Fig 4B shows current traces from the 100-ms pulse paradigm in the absence and presence of lidocaine (100 µmol/L) at two time bases and current gains in response to test pulses to -10 mV. The maintained current traces were averaged to improve the signal-to-noise ratio. The upper row shows hH1 channel activity, and the lower row shows KPQ channel activity. The peak current at the beginning of the test pulse was inhibited by 35% for hH1 and 31% for KPQ channels. In the same experiment, maintained current, prominent in this example only for KPQ channels (Fig 4B, right), is 70% blocked by lidocaine. The results of this experiment were typical of experimental results from a large number of cells, as summarized in Fig 4C. The bar graph includes data from the 100-ms and 40-ms pulse paradigms, which, as noted above, provided the same experimental results. There was no significant difference in tonic block of peak wild-type (hH1) and mutant (KPQ) channel current, but block of maintained KPQ channel current was significantly greater than block of peak current through either wild-type or mutant channels.
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Discussion |
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The important discovery that one form of LQT-3 is linked to a specific mutation of the human heart Na+ channel
subunit by Wang et al11 has allowed the direct testing of specific therapeutic approaches to the management of clinically relevant arrhythmias based on the functional consequences encoded by the genetic message. Our results, in which recombinant mutant (KPQ) channels have been expressed for the first time in mammalian cells, confirm the finding of Bennett et al22 that the KPQ mutation enhances maintained Na+ channel current during the delicate plateau period of the cardiac action potential. Although this maintained current is only a small fraction (4%, Fig 1) of peak excitatory Na+ channel current, because of the unique high input impedance of the cardiac action potential plateau,32 it will prolong the action potential and underlie the clinical phenotype used, in part, to identify patients with LQT-3.33 We also find, however, marked differences in the kinetics of channel inactivation that are caused by the KPQ mutation. The onset of and recovery from inactivation is speeded by the mutation, in contrast with the results of Bennett et al,22 in which only the time course of the onset of inactivation was speeded by the KPQ mutation. In the absence of drug, because we find that mutant channels recover from inactivation faster than wild-type channels, our results predict that hearts of carriers of the SCN5A mutation will have shorter relative refractory periods and consequently be more vulnerable to premature excitation.
Our results also show that the antiarrhythmic drug lidocaine modulates mutant channel activity in two manners that will have important implications for treatment of LQT-3. First, tonic block by lidocaine is greater for the maintained current than for peak current in the mutant channels. Thus preferential block of maintained current by lidocaine is a mechanism by which this Class IB drug can target dysfunctional channel properties that underlie prolongation of the ventricular action potential, the clinical phenotype of LQT-3. Lidocaine block of native Na+ channels is known to depend on the state of the Na+ channel and is more pronounced for channels in the inactivated state.23 24 25 Bennett et al22 have shown that the KPQ mutation causes mutant Na+ to enter an altered gating mode in which mutant channels reopen from the inactivated state, producing bursts of channel openings during maintained depolarization. This contrasts markedly with the activity of wild-type channels, which open briefly, inactivate, and fail to reopen during maintained depolarization. Mutant channels that make transitions between the inactivated state and a mode of gating in which bursts of activity occur for prolonged periods could very likely be blocked by lidocaine and other Class IB agents with higher affinity than channels that do not enter this gating mode. Second, in the presence of lidocaine, mutant Na+ channel kinetics of recovery from inactivation and depolarization-induced block approach the time course of drug-free wild-type channels. Thus, lidocaine treatment could additionally reduce the risk of premature excitation in SCN5A mutant carriers by slowing recovery from inactivation.
We have measured lidocaine block of peak current during infrequent application of test depolarization, which is consistent with rested-state block of channels. This type of block has been shown previously34 to be 
30-fold less potent than lidocaine block of inactivated channels. Therefore, the KPQ mutation, which causes channels to exit the inactivated state and enter a bursting-gating mode, most likely creates conditions in which lidocaine preferentially inhibits channel activity underlying maintained macroscopic current by virtue of the change in the state of the channels caused by the inherited mutation. Because we find that peak Na+ channel current, which underlies cardiac impulse conduction and the QRS complex of the electrocardiogram, is less sensitive to lidocaine block than maintained current, our results predict that, for carriers of this specific SCN5A mutation, pharmacological shortening of the QT interval should be possible with minimal side effects on excitation spread in the heart as measured by the QRS complex. It must, of course, be emphasized that we investigated the effects of lidocaine at a concentration (100 µmol/L) that ranges from 5 to 20 times higher than typical therapeutic concentrations.35 Hence, extrapolation of our results directly to clinical use must be made with caution. Future investigations will determine whether discrimination between wild-type and mutant channels can be improved by other Na+ channel blocking agents, and whether or not the therapeutic strategies predicted from electrophysiological studies of recombinant channels are in fact confirmed in clinical studies with drug concentrations that lie within a therapeutic concentration range.
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Acknowledgments |
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This work was supported by US Public Health Service grant HL 21922-15. We thank Dr Mark Keating for generously providing us with the clones for hH1 and
KPQ channels. Received November 8, 1995; accepted March 29, 1996.
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References |
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J. D. Malhotra, C. Chen, I. Rivolta, H. Abriel, R. Malhotra, L. N. Mattei, F. C. Brosius, R. S. Kass, and L. L. Isom Characterization of Sodium Channel {{alpha}}- and {beta}-Subunits in Rat and Mouse Cardiac Myocytes Circulation, March 6, 2001; 103(9): 1303 - 1310. [Abstract] [Full Text] [PDF]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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Y. A. Kuryshev, A. M. Brown, L. Wang, C. R. Benedict, and D. Rampe Interactions of the 5-Hydroxytryptamine 3 Antagonist Class of Antiemetic Drugs with Human Cardiac Ion Channels J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 614 - 620. [Abstract] [Full Text]
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H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]
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X. H. T. Wehrens, H. Abriel, C. Cabo, J. Benhorin, and R. S. Kass Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel {alpha}-Subunit : A Computational Analysis Circulation, August 1, 2000; 102(5): 584 - 590. [Abstract] [Full Text] [PDF]
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J. Benhorin, R. Taub, M. Goldmit, B. Kerem, R. S. Kass, I. Windman, and A. Medina Effects of Flecainide in Patients With New SCN5A Mutation : Mutation-Specific Therapy for Long-QT Syndrome? Circulation, April 11, 2000; 101(14): 1698 - 1706. [Abstract] [Full Text] [PDF]
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 K. Ono, T. Kaku, N. Makita, A. Kitabatake, and M. Arita Selective Block of Late Currents in the Delta KPQ Na+ Channel Mutant by Pilsicainide and Lidocaine with Distinct Mechanisms Mol. Pharmacol., February 1, 2000; 57(2): 392 - 400. [Abstract] [Full Text]
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T. Nagatomo, C. T. January, and J. C. Makielski Preferential Block of Late Sodium Current in the LQT3 Delta KPQ Mutant by the Class IC Antiarrhythmic Flecainide Mol. Pharmacol., January 1, 2000; 57(1): 101 - 107. [Abstract] [Full Text]
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 F. Lehmann-Horn and K. Jurkat-Rott Voltage-Gated Ion Channels and Hereditary Disease Physiol Rev, October 1, 1999; 79(4): 1317 - 1372. [Abstract] [Full Text] [PDF]
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 Gene-specific lethality of arrhythmic events in the long QT syndrome? A message from the International Registry Eur. Heart J., August 2, 1999; 20(16): 1137 - 1139. [PDF]
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J. R. Balser Structure and function of the cardiac sodium channels Cardiovasc Res, May 1, 1999; 42(2): 327 - 328. [Abstract] [Full Text] [PDF]
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R. Chandra, V. S. Chauhan, C.F. Starmer, and A. O. Grant {beta}-adrenergic action on wild-type and KPQ mutant human cardiac Na+ channels: shift in gating but no change in Ca2+: Na+ selectivity Cardiovasc Res, May 1, 1999; 42(2): 490 - 502. [Abstract] [Full Text] [PDF]
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 H. B. Nuss, E. Marbán;, C. W. Balke, L. Goldman, R. Aggarwal, S. R. Shorofsky;, J. dos Santos Cruz, L. F. Santana, C. A. Frederick, L. L. Isom, et al. Whether "Slip-Mode Conductance" Occurs Science, April 30, 1999; 284(5415): 711a - 711. [Full Text]
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T. Nagatomo, Z. Fan, B. Ye, G. S. Tonkovich, C. T. January, J. W. Kyle, and J. C. Makielski Temperature dependence of early and late currents in human cardiac wild-type and long Q-T Delta KPQ Na+ channels Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2016 - H2024. [Abstract] [Full Text] [PDF]
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 R. L. Sah, R. G. Tsushima, and P. H. Backx Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation Am J Physiol Cell Physiol, August 1, 1998; 275(2): C389 - C400. [Abstract] [Full Text] [PDF]
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 R. H. An, X. L. Wang, B. Kerem, J. Benhorin, A. Medina, M. Goldmit, and R. S. Kass Novel LQT-3 Mutation Affects Na+ Channel Activity Through Interactions Between {alpha}- and ß1-Subunits Circ. Res., July 27, 1998; 83(2): 141 - 146. [Abstract] [Full Text] [PDF]
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R. Chandra, C. F. Starmer, and A. O. Grant Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells Am J Physiol Heart Circ Physiol, May 1, 1998; 274(5): H1643 - H1654. [Abstract] [Full Text] [PDF]
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N. G. Kambouris, H. B. Nuss, D. C. Johns, G. F. Tomaselli, E. Marban, and J. R. Balser Phenotypic Characterization of a Novel Long-QT Syndrome Mutation (R1623Q) in the Cardiac Sodium Channel Circulation, February 24, 1998; 97(7): 640 - 644. [Abstract] [Full Text] [PDF]
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R. Dumaine and G. E. Kirsch Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H477 - H487. [Abstract] [Full Text] [PDF]
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 I. Rivolta, H. Abriel, M. Tateyama, H. Liu, M. Memmi, P. Vardas, C. Napolitano, S. G. Priori, and R. S. Kass Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes J. Biol. Chem., August 10, 2001; 276(33): 30623 - 30630. [Abstract] [Full Text] [PDF]
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H. Abriel, C. Cabo, X. H. T. Wehrens, I. Rivolta, H. K. Motoike, M. Memmi, C. Napolitano, S. G. Priori, and R. S. Kass Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel Circ. Res., April 13, 2001; 88(7): 740 - 745. [Abstract] [Full Text] [PDF]
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