Na v Channel Complex Heterogeneity
2014; Lippincott Williams & Wilkins; Volume: 130; Issue: 2 Linguagem: Inglês
10.1161/circulationaha.114.010867
ISSN1524-4539
AutoresThomas J. Hund, Peter J. Mohler,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoHomeCirculationVol. 130, No. 2Nav Channel Complex Heterogeneity Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNav Channel Complex HeterogeneityNew Targets for the Treatment of Arrhythmia? Thomas J. Hund, PhD and Peter J. Mohler, PhD Thomas J. HundThomas J. Hund From The Ohio State University Wexner Medical Center, Columbus. and Peter J. MohlerPeter J. Mohler From The Ohio State University Wexner Medical Center, Columbus. Originally published3 Jun 2014https://doi.org/10.1161/CIRCULATIONAHA.114.010867Circulation. 2014;130:132–134Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 8, 2014: Previous Version 1 Despite major breakthroughs in cardiovascular diagnostics and therapies over the past century, diseases of the heart remain a leading cause of death in the United States, nearing 600 000 deaths per year.1 Most of these deaths (200 000–400 000 per year)2 are due to cardiac arrhythmia in which syncope and sudden death are often the first manifestations of heart disease. Foundational work by Wang et al3 in the mid-1990s cemented the critical role of ion channel dysfunction in human arrhythmia. Today, we know that ≈35% of sudden unexplained death and ≈20% of sudden infant death syndrome cases may be explained by mutations in cardiac ion channels (cardiac channelopathies).4,5 Furthermore, defects in ion channel function have widely been observed in common forms of heart failure.6 This year marks the 25th anniversary of publication of the preliminary Cardiac Arrhythmia Suppression Trial (CAST) findings in the New England Journal of Medicine.7 Here, we discuss new findings reported by Shy et al8 on Nav channel macromolecular complexes reported in this issue of Circulation and reflect on lessons learned in the ensuing years after CAST that may help propel advances in treatment of cardiovascular disease over the next quarter-century.Article see p 147Defects in voltage-gated sodium (Nav) channels are among the best characterized of the cardiac channelopathies. Nav channel complexes are composed of a large ≈260-kDa pore-forming α-subunit and an associated auxiliary β-subunit. In humans, Nav α-subunits are encoded by 9 genes, whereas 4 genes encode Nav β-subunits.9 Beyond heart, Nav channel gene defects are linked to a host of excitable cell phenotypes, including epilepsy and seizures, myotonia, and erythromelalgia.9 Although multiple Nav channel α-subunits are expressed in heart, Nav1.5 (SCN5A) is the primary α-subunit responsible for conducting inward sodium current (INa) at the outset of the action potential (phase 0). Human SCN5A gene defects leading to alterations in Nav1.5-depedent INa are now linked to many cardiac arrhythmia phenotypes, including sick sinus syndrome, atrial fibrillation, progressive and nonprogressive heart block, type 3 long-QT syndrome, and Brugada syndrome.The Nav1.5 channel protein consists of 4 membrane domains (DI–DIV), with each domain made up of 7 transmembrane spanning helixes (S1–S6; Figure). Each membrane-embedded helix serves specific roles to regulate Na+ flux through the channel. For example, S5/S6 helixes form the Na+ conductance pore, whereas the S4 helixes serve as a voltage sensor to facilitate channel activation.9 Cytoplasmic loops connect DI through DIV, with additional intracellular domains at both the N- and C-termini of the protein (Figure). To date, the majority of arrhythmia variants are located in regions of the SCN5A gene that affect channel biophysical properties. However, advances in genetics, small-animal physiology, signaling, and molecular biology over the past decade have powered new studies highlighting the role of Nav1.5-associated proteins in the regulation of INa, as well as dysfunction in heart failure and arrhythmia. In fact, these findings are not limited to Nav1.5 but have been illustrated for voltage-gated potassium and calcium channels, as well as membrane transporters and non–voltage-gated channels.11Download figureDownload PowerPointFigure. Voltage-gated Na+ channel structure and interaction proteins. Nav protein partners include the adapter protein ankyrin-G, the ubiquitin ligase Nedd4-2 (neural precursor cell–expressed developmentally downregulated protein 4), calmodulin, MOG1 (multicopy suppressor of Gsp1), 14-3-3n, PTP-H1 (protein tyrosine phosphatase H1), FGF12B (fibroblast growth factor homologous factor 12), syntrophin, and SAP97 (synapse-associated protein 97).10 The PDZ-domain binding motif (SIV) in the C terminus controls regulation with PDZ-domain–containing proteins (eg, syntrophin and SAP97).Targeting Nav1.5 to prevent arrhythmias has a troubled history, exemplified by CAST in which the Na+ channel–blocking agents encainide and flecainide increased mortality compared with placebo in patients after myocardial infarction.7 Despite the fact that 25 years have passed since this landmark report, the field struggles to move beyond lessons learned about the proarrhythmic potential of antiarrhythmia drugs. The study from Shy and colleagues8 in this issue of Circulation may suggest a way forward by adding to mounting evidence that multiple Nav1.5 populations exist within the cardiomyocyte. These populations differ not only by location (eg, intercalated disk, transverse tubule, lateral membrane) but also by the nature of their interacting partners, regulation, and likely drug sensitivity.12 In fact, multiple Nav1.5 macromolecular complexes form as a result of a large number of interactions between Nav1.5 and accessory, adapter, cytoskeletal, and regulatory proteins (Figure).10 Importantly, Nav1.5 interacts with different partners, depending on its location in the cell. Functionally, this contributes to a heterogeneous population of Nav1.5 within the cell. At the intercalated disk where cells are electrically and mechanically coupled, the Nav1.5 macromolecular complex includes the adapter protein ankyrin-G, as well as calcium/calmodulin-dependent protein kinase II (CaMKII) via interaction with βIV-spectrin.13 Nav1.5 is also found at transverse tubules, together with ankyrin-G.14 In fact, SCN5A mutations that block ankyrin-G binding alter Nav1.5 membrane trafficking and are associated with Brugada syndrome.14 Other studies have identified possibly a second population of channels at the intercalated disk that interact with the adapter protein synapse-associated protein 97 (SAP97) via a PDZ-domain (named for its presence in the postsynaptic density protein PSD95, the disk large tumor suppressor Dlg1, and zonula occludens-1 [ZO1])–binding motif in the Nav1.5 C terminus.15 Potential interaction between Nav1.5 and both connexin43 and plakophilin-2 at the intercalated disk has also been reported.16 At the lateral membrane, recent work by Petitprez and colleagues15 has identified an important role for the syntrophin/dystrophin complex in targeting Nav1.5.The study from Shy and colleagues8 in this issue of Circulation provides important new in vivo data on the characteristics of distinct Nav1.5 complexes at the intercalated disk and lateral membrane, highlighting the structural and functional differences between at least 2 of the potential Nav1.5 populations. On the basis of the previously observed interaction of Nav1.5 with PDZ domain–bearing proteins at both the lateral membrane (syntrophin) and intercalated disk (SAP97), the authors developed a knock-in mouse that expresses Nav1.5 lacking the PDZ domain-binding motif (ΔSIV). The authors report a significant decrease in Na+ current in ventricular myocytes from the ΔSIV mice compared with wild-type mice, coupled with a loss of Nav1.5 at the lateral membrane,8 consistent with previous reports.15 Notably, Nav1.5 at the intercalated disk was unaffected in ΔSIV myocytes, an unexpected finding given that prior studies in myocytes with acute knockdown of SAP97 expression showed disrupted Nav1.5 intercalated disk targeting.15,17 These new in vivo data strongly support a PDZ-domain–dependent interaction for lateral membrane Nav1.5 targeting. Conversely, these in vivo findings clearly demonstrate that Nav1.5 is targeted to the intercalated disk independently of the PDZ-domain protein association. Finally, the authors report a de novo human arrhythmia mutation in the Nav1.5 PDZ-domain–binding motif that negatively affects partner interaction and Na+ channel function, suggesting a role for this channel population in human cardiovascular disease.In light of growing evidence that multiple Nav channel complexes exist in the myocyte, can we exploit the unique characteristics of these distinct populations for therapeutic advantage? Currently, Na+ channel–blocking drugs that target the late (persistent) phase of Na+ current (as opposed to the rapid component) are gaining favor as potential agents to treat cardiovascular disease/arrhythmias.18 For example, the antianginal Na+ channel blocker ranolazine with unique kinetics that preferentially target the late Na+ current has proven effective in preventing arrhythmias and improving outcomes in a number of animal models and is in limited clinical trials for heart failure.18 Going forward, can we apply these findings to devise new antiarrhythmia strategies based on the distinct profile of a specific Na+ channel population? In other words, are there unexplored avenues for preventing arrhythmias/disease by targeting specific Na+ channel complexes? To answer this question, it is important to consider the cellular factors that regulate the cardiac Nav1.5 late current. Mounting evidence supports a central role for the multifunctional serine/threonine CaMKII in controlling the magnitude of the late current through direct phosphorylation of the Na+ channel.19,20 CaMKII is preferentially targeted to Nav1.5 at the intercalated disk via direct interaction with the actin-associated cytoskeletal protein βIV-spectrin.13 Furthermore, targeted disruption of the spectrin/CaMKII interaction decreases late Na+ current without affecting the peak.13 Together with the new data from Shy and colleagues8 and prior functional work by Lin et al,12 these findings suggest that perhaps by targeting intercalated disk Nav1.5 (eg, altering spectrin levels/interaction with CaMKII) we can preferentially target the proarrhythmic component of the Na+ current while protecting/maintaining key populations of Nav1.5 required for cardiac conductionAs the 25th anniversary of the CAST publication comes and goes, it is appropriate to reflect on the importance of this work and the many ways it has affected basic and translational cardiac arrhythmia research. At the same time, it is important to recognize the sea change that has transpired in our understanding of Nav channel biology and our ability to manipulate channel function. It is our expectation that major therapeutic advances will be made over the next 25 years by focusing on specific Nav channel macromolecular complexes to fine-tune Nav function.Sources of FundingThis work was supported by National Institutes of Health grants HL084583, HL083422, and HL114383 to Dr Mohler; National Institutes of Health grant HL114893 to Dr Hund; the American Heart Association (Dr Mohler); and the James S. McDonnell Foundation (Dr Hund).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Peter J. Mohler, PhD, The Ohio State University Wexner Medical Center, The Dorothy M. Davis Heart & Lung Research Institute, 473 W 12th Ave, Columbus, OH 43210. E-mail [email protected]References1. 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Veeraraghavan R, Hoeker G, Alvarez-Laviada A, Hoagland D, Wan X, King D, Sanchez-Alonso J, Chen C, Jourdan J, Isom L, Deschenes I, Smyth J, Gorelik J, Poelzing S and Gourdie R (2018) The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation, eLife, 10.7554/eLife.37610, 7 Hund T and Mohler P (2018) Function and Dysfunction of Ion Channel Membrane Trafficking and Posttranslational Modification Cardiac Electrophysiology: From Cell to Bedside, 10.1016/B978-0-323-44733-1.00023-7, (212-218), . Bengel P, Ahmad S and Sossalla S (2017) Inhibition of Late Sodium Current as an Innovative Antiarrhythmic Strategy, Current Heart Failure Reports, 10.1007/s11897-017-0333-0, 14:3, (179-186), Online publication date: 1-Jun-2017. Smith S, Hughes L, Kline C, Kempton A, Dorn L, Curran J, Makara M, Webb T, Wright P, Voigt N, Binkley P, Janssen P, Kilic A, Carnes C, Dobrev D, Rasband M, Hund T and Mohler P (2016) Dysfunction of the β 2 -spectrin-based pathway in human heart failure , American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00875.2015, 310:11, (H1583-H1591), Online publication date: 1-Jun-2016. Nerbonne J (2016) Molecular Basis of Functional Myocardial Potassium Channel Diversity, Cardiac Electrophysiology Clinics, 10.1016/j.ccep.2016.01.001, 8:2, (257-273), Online publication date: 1-Jun-2016. Unudurthi S and Hund T (2016) Late sodium current dysregulation as a causal factor in arrhythmia, Expert Review of Cardiovascular Therapy, 10.1586/14779072.2016.1155451, 14:5, (545-547), Online publication date: 3-May-2016. Choi J, Wang C, Thomas M, Pitt G and Zhang Z (2016) α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current, PLOS ONE, 10.1371/journal.pone.0152355, 11:3, (e0152355) Frolov R and Weckström M (2016) Harnessing the Flow of Excitation Ion Channels as Therapeutic Targets, Part A, 10.1016/bs.apcsb.2015.11.001, (25-95), . Makara M, Curran J, Little S, Musa H, Polina I, Smith S, Wright P, Unudurthi S, Snyder J, Bennett V, Hund T and Mohler P (2014) Ankyrin-G Coordinates Intercalated Disc Signaling Platform to Regulate Cardiac Excitability In Vivo, Circulation Research, 115:11, (929-938), Online publication date: 7-Nov-2014. July 8, 2014Vol 130, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.114.010867PMID: 24895456 Originally publishedJune 3, 2014 KeywordsEditorialsarrhythmias, cardiacPDF download Advertisement SubjectsArrhythmias
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