Sodium “Channelopathies” and Sudden Death
1999; Lippincott Williams & Wilkins; Volume: 85; Issue: 9 Linguagem: Inglês
10.1161/01.res.85.9.872
ISSN1524-4571
Autores Tópico(s)Receptor Mechanisms and Signaling
ResumoHomeCirculation ResearchVol. 85, No. 9Sodium "Channelopathies" and Sudden Death Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSodium "Channelopathies" and Sudden Death Must You Be So Sensitive? Jeffrey R. Balser Jeffrey R. BalserJeffrey R. Balser From the Departments of Anesthesiology and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn. Originally published29 Oct 1999https://doi.org/10.1161/01.RES.85.9.872Circulation Research. 1999;85:872–874Recognizing the diverse cascade of ionic currents that compose the cardiac action potential, and the wisdom of nature to provide redundant systems that protect us from environmental insults, one wonders whether the heart could really notice the aberrant behavior of a single group of excitable proteins. Nonetheless, the first linkage of Na+ channel mutations to an inherited form of the long-QT syndrome (LQT3)1 made it amply clear that badly behaved Na+ channels are not well tolerated. Even more surprising were the functional studies of channels carrying the LQT3-linked mutations. Although Na+ channels normally open only briefly (and then inactivate) as the action potential commences, channels carrying these autosomal dominant mutations occasionally "forget" to inactivate, causing a small inward current that persists during the action potential plateau.2 It appears that this excess current, essentially a gain of Na+ channel function, delays cellular repolarization, prolongs the QT interval, and predisposes patients to torsades de pointes.Surprisingly, the size of this "pathologic" current is minuscule compared with the overall size of the Na+ current (INa) in its full glory (so-called "peak INa"). For the 1505-1507 ΔKPQ III-IV interdomain linker deletion mutant,3 and the recently identified C-terminus mutation E1784K,4 the sustained current accounts for only ≈2% of the peak INa. Even more striking, the R1644H long-QT mutation produces a sustained current that is ≈0.5% of the peak current.35 Nonetheless, a mechanistic linkage between this small defect, action potential prolongation, and proarrhythmic triggered activity ("EADs") was recently validated in an elegant quantitative model,6 a result that expanded our intuition for the nonlinear relationship between Na+ channel function and the risk of sudden death.In this context, it was not altogether surprising to learn that another class of inherited ventricular arrhythmias, collectively known as the "Brugada syndrome,"7 traces its lineage to the Na+ channel. However, in contrast to the long-QT mutations, which made heuristic (if not quantitative) sense, the functional effects of Brugada syndrome mutations have been diverse and puzzling. In the first report,8 two mutations were identified (a frameshift and a splice donor) that rendered the Na+ channel entirely nonfunctional. This would imply that a loss of Na+ channel function is conducive to the Brugada syndrome, in contrast to the gain of function mutations linked to the long-QT syndrome. However, functional studies of a third mutation (T1620M) that cosegregated with a small Brugada kindred provided an unexpected result. The mutation did not suppress INa but rather seemed to destabilize the inactivation process, reminiscent of the long-QT mutations. Although a plateau of noninactivating current was not identified, the mutation shifted the voltage dependence of steady-state inactivation to more positive membrane potentials and sped recovery from inactivation by nearly 30%, thereby increasing the overall availability of Na+ channels.These T1620M functional effects have remained unreconciled with the clinical syndrome, as the evidence supporting a loss of Na+ channel function in the Brugada phenotype has strengthened. Two additional mutations in the III-IV interdomain linker (R1512W) and the C terminus (A1924T) have recently been linked to the Brugada syndrome.9 Although these mutations do not eliminate channel function, they shift the voltage dependence of steady-state inactivation to more negative membrane potentials, thereby reducing the "functional" availability of channels to open when the membrane is depolarized. In addition, it is increasingly clear that Na+ channel blocking agents exacerbate the ECG pattern of Brugada syndrome10 and in some cases may elicit both the "Brugada ECG" and ventricular fibrillation de novo.1112Mechanistic insight into how a loss of Na+ channel function (either genetic or pharmacological) may induce ventricular fibrillation predates the Brugada syndrome-Na+ channel linkage studies.1314 In short, the duration of the epicardial myocardial cell action potential is more "sensitive" to a reduction in INa than is the endocardial action potential. In the epicardium, a prominent transient outward K+ current (Ito) counterbalances INa during the earliest phases of the action potential; hence, any misadventure (ischemia,15 class I drugs,1216 or mutations16 ) that suppresses INa can trigger "all-or-none" repolarization in the epicardium, grotesquely shrinking the duration of the epicardial action potential. This condition creates a temporal imbalance between endocardial and epicardial repolarization, and such heterogeneity across the right ventricular outflow tract may engender reentry and thus explain the ECG pattern and arrhythmic manifestations of the Brugada syndrome.16 This mechanism may also underlie the toxicity of Na+ channel blockers in CAST (Cardiac Arrhythmia Suppression Trial), particularly because that outcome seems to have been exaggerated by ischemia.17Given all of the momentum swinging toward "loss of Na+ channel function" as the molecular basis of the Brugada phenotype, how can we rationalize the gain of function originally noted for T1620M? The report by Dumaine and coworkers18 in this issue of Circulation Research provides an answer, and at the same time, reminds us of the surprising (and even nonlinear) effect experimental conditions may impose on ion channel functional behavior. Most would concede that the rapid character of the Na+ current poses a challenge when attempting to accurately measure the channel gating kinetics using whole-cell voltage-clamp recordings at "physiological" (≈37°C) temperatures. This technical difficulty may be managed by making measurements at lower temperatures that slow the gating kinetics and then extrapolating the results to warmer temperatures. However, a more physiological but technically demanding approach is to optimize the voltage-clamp conditions at higher temperatures. In the present study, this was accomplished partly by using cultured mammalian cells (tsA-201) instead of Xenopus oocytes. Conditions were further improved by juggling the ionic conditions (reducing the Na+ gradient by raising [Na+]i to 35 mmol/L) and by reducing the amount of transfected cDNA to reduce the overall size of the current. In addition, low-resistance patch electrodes (0.6 to 1.0 MΩ) were used to minimize voltage errors.Under these conditions, with the temperature raised to 32°C, the effects of T1620M on Na+ channel gating were vastly different than at room temperature. In particular, the mutation hastened the decay of INa by a factor of ≈2. As the temperature was further raised to approach 42°C, a condition that no doubt pushes the limits of clamp accuracy despite efforts to optimize, the gradient in decay rate between wild type and mutant persisted and may even have increased. In addition, the kinetics of recovery from fast inactivation were slowed in T1620M at 32°C, in sharp contrast to the hastening of recovery observed at room temperature in this study and in the original recordings of T1620M in Xenopus oocytes.8 At warm temperatures, the voltage dependence of activation was also shifted to more positive membrane potentials (≈+10 mV). Each of these gating effects would tend to decrease the magnitude of INa during an action potential, suggesting that T1620M actually renders functional effects on INa that are directionally consistent with the other mutations and drug effects linking Na+ channels to the Brugada syndrome.It is worth noting that T1620 sits on the external linker between the third and fourth (S3 and S4) transmembrane segments in domain IV. The outermost S4 arginine (R1623), only 3 residues C-terminal to this position, figures critically in the voltage-dependent gating function of the S4 segment, tightly coupling inactivation to activation.1920 Intriguingly, a charge deletion at this position (R1623Q) has been implicated in a sporadic case of the long-QT syndrome in Japan,21 and functional studies show that the R1623Q gating phenotype is a mirror image of T1620M: the decay of whole-cell INa is slowed.2223 The opposite effects of these mutations, despite their close proximity, may be surprising. However, although III-IV linker mutations are known to disrupt inactivation24 and clinically are linked to a long-QT phenotype,5 a recently identified Brugada syndrome mutation (R1512W) stabilized inactivation and lies in the III-IV linker only 5 residues away from the ΔKPQ long-QT deletion.9 The diverse functional effects of these vicinal mutations underscore the complex relationship between ion channel structure at an amino acid level, as well as functional behavior at a whole-protein level.Dumaine et al18 rose to the challenge of simulating the functional effects of T1620M at warm temperatures on the cardiac action potential. Using a modified version of the action potential model developed by Luo and Rudy,25 their findings suggest that the right ventricular epicardium may be more sensitive than the endocardium or left ventricular epicardium to hastening the INa decay rate. Although this simulation empirically confirms that "loss of function" is sufficient to shorten the epicardial action potential, it may fall short of convincing us that the observed increase in the INa decay rate is singularly responsible for the clinical phenotype. The empiric 2-fold change in the rate constants for inactivation speeds INa decay but also reduces the simulated peak INa by 32%, an effect that might either prevent (per the authors' speculation)18 or exacerbate the clinical phenotype. For example, we know that other mutations that eliminate Na+ channel function (and thus reduce peak INa) also produce the Brugada syndrome.8 It remains to be shown whether reduced peak INa is a genuine feature of T1620M and whether the other gating effects of the mutation (activation and recovery from fast inactivation) are also important. Additionally, as the authors suggest, single-channel experiments will be required to determine whether the mutation-induced speeding of INa decay actually results from an effect on inactivation gating, or rather from more rapid activation gating.26Given the highly nonlinear relationship between ion channel gating and transmembrane voltage, the challenges in implementing action potential models that incorporate subtle ion channel gating effects in a manner that recapitulates physiology in a genuine way are formidable. Recent studies linking complex ion channel functional defects to the action potential configuration using computational approaches are providing new insights into the factors that critically influence the long-QT phenotype (gating behavior, cell layers, pacing rate).627 Moreover, as the number of ion channel mutations and "therapeutic" agents linked to cardiac arrhythmias exponentially expand, strategies that allow us to view the downstream effects of miniscule changes in ion channel function on the electrophysiology of the whole heart will become ever more essential.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Support was provided by the National Institutes of Health (R01 GM56307, P01 HL46681). Dr Balser holds the James Taloe Gwathmey Clinician Scientist Chair at Vanderbilt University.FootnotesCorrespondence to Jeffrey R. 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References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited ByYagihara N, Watanabe H, Barnett P, Duboscq‐Bidot L, Thomas A, Yang P, Ohno S, Hasegawa K, Kuwano R, Chatel S, Redon R, Schott J, Probst V, Koopmann T, Bezzina C, Wilde A, Nakano Y, Aiba T, Miyamoto Y, Kamakura S, Darbar D, Donahue B, Shigemizu D, Tanaka T, Tsunoda T, Suda M, Sato A, Minamino T, Endo N, Shimizu W, Horie M, Roden D and Makita N (2016) Variants in the 5A Promoter Associated With Various Arrhythmia Phenotypes, Journal of the American Heart Association, 5:9, Online publication date: 1-Sep-2016. 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October 29, 1999Vol 85, Issue 9 Advertisement Article Information Metrics © 1999 American Heart Association, Inc.https://doi.org/10.1161/01.RES.85.9.872 Originally publishedOctober 29, 1999 KeywordsNa+ channelinactivationBrugada syndromeantiarrhythmic drugPDF download Advertisement
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