Modulation of late sodium current by Ca<sup>2+</sup>, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences

Maltsev, Victor A.; Reznikov, Vitaliy; Undrovinas, Nidas A.; Sabbah, Hani N.; Undrovinas, A. I.

doi:10.1152/ajpheart.00484.2007

Cited by 122 publications

(120 citation statements)

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“…[65][66][67] It is widely accepted that signalling through the Ca 2+ -CaM-CaMKII pathway facilitates the sodium current, especially its late component. 16,65,68 The Ca 2+ dependent regulation modifies mainly the inactivation of the sodium channels. Ca 2+ or CaM binding to the channel causes a~5 mV shift in the steady-state inactivation (SSI) towards more positive voltages.…”

Section: +mentioning

confidence: 99%

The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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Large and growing body of data suggest that an increased late sodium current (I Na,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how I Na,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase I Na,late in cardiac disease, and also to describe how the up-regulated I Na,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of I Na,late -modifying drugs in heart failure, on the basis of experimental and preclinical data.

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Section: +mentioning

confidence: 99%

The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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“…With respect to late I Na during the action potential plateau, several studies have indicated that this current is increased in human and canine heart failure (209,211), possibly resulting from a slowing of inactivation kinetics and a shift of the voltage dependence of steady-state inactivation, as mediated by intracellular Ca 2ϩ /CaMKII signaling (140,214). (207,208), whereas I Ks but not I Kr was downregulated in all layers of the left ventricular myocardium in a canine model of tachycardiainduced heart failure (133).…”

Section: Role Of Cardiac Dynamics In the Generation Of Ventricular Armentioning

confidence: 99%

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

Cherry

Fenton

Gilmour

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cherry EM, Fenton FH, Gilmour RF Jr. Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective. Am J Physiol Heart Circ Physiol 302: H2451-H2463, 2012. First published March 30, 2012 doi:10.1152/ajpheart.00770.2011Defining the cellular electrophysiological mechanisms for ventricular tachyarrhythmias is difficult, given the wide array of potential mechanisms, ranging from abnormal automaticity to various types of reentry and kk activity. The degree of difficulty is increased further by the fact that any particular mechanism may be influenced by the evolving ionic and anatomic environments associated with many forms of heart disease. Consequently, static measures of a single electrophysiological characteristic are unlikely to be useful in establishing mechanisms. Rather, the dynamics of the electrophysiological triggers and substrates that predispose to arrhythmia development need to be considered. Moreover, the dynamics need to be considered in the context of a system, one that displays certain predictable behaviors, but also one that may contain seemingly stochastic elements. It also is essential to recognize that even the predictable behaviors of this complex nonlinear system are subject to small changes in the state of the system at any given time. Here we briefly review some of the short-, medium-, and long-term alterations of the electrophysiological substrate that accompany myocardial disease and their potential impact on the initiation and maintenance of ventricular arrhythmias. We also provide examples of cases in which small changes in the electrophysiological substrate can result in rather large differences in arrhythmia outcome. These results suggest that an interrogation of cardiac electrical dynamics is required to provide a meaningful assessment of the immediate risk for arrhythmia development and for evaluating the effects of putative antiarrhythmic interventions.alternans; dynamics; spiral waves; ventricle THIS REVIEW ARTICLE is part of a collection on Electrophysiology and Excitation-Contraction Coupling. Other articles appearing in this collection, as well as a full archive of all Review collections, can be found online at http://ajpheart. physiology.org/.

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“…Direct interaction between cytoplasmic COOH terminus (CT) domain of Na v 1.1 with Na v ␤ 1 and Na v ␤ 3 has recently been demonstrated (39) and thus offers possible molecular mechanisms for I NaL modulation by Na v ␤ 1 found here (if similar interactions exist for Na v 1.5). The role of the CT to regulate Na v 1.5 inactivation has been recently suggested via the Ca 2ϩ -calmodulin-dependent interaction with the III-IV linker, responsible for the initial fast inactivation (1, 33), and has been elucidated for I NaL regulation (20). It has been also suggested that the Na v ␤ 1 subunit modulates Na v 1.5 inactivation via interaction with the microtubule cytoskeleton (4).…”

Section: Molecular Mechanisms Of I Nal Modulation By Na V ␤ 1 and Na mentioning

confidence: 99%

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

Mishra

Undrovinas

Maltsev

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Mishra S, Undrovinas NA, Maltsev VA, Reznikov V, Sabbah HN, Undrovinas A. Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure. Am J Physiol Heart Circ Physiol 301: H1596 -H1605, 2011. First published June 24, 2011 doi:10.1152/ajpheart.00948.2009.-The emerging paradigm for Na ϩ current in heart failure (HF) is that its transient component (INaT) responsible for the action potential (AP) upstroke is decreased, whereas the late component (INaL) involved in AP plateau is augmented. Here we tested whether Nav␤1-and Nav␤2-subunits can modulate INaL parameters in normal and failing ventricular cardiomyocytes (VCMs). Chronic HF was produced in nine dogs by multiple sequential coronary artery microembolizations, and six dogs served as a control. INa and APs were measured by the whole cell and perforated patch-clamp in freshly isolated and cultured VCMs, respectively. INaL was augmented with slower decay in HF VCMs compared with normal heart VCMs, and these properties remained unchanged within 5 days of culture. Posttranscriptional silencing SCN1B and SCN2B were achieved by virally delivered short interfering RNA (siRNA) specific to Nav␤1 and Nav␤2. The delivery and efficiency of siRNA were evaluated by green fluorescent protein expression, by the real-time RT-PCR, and Western blots, respectively. Five days after infection, the levels of mRNA and protein for Nav␤1 and Nav␤2 were reduced by Ͼ80%, but mRNA and protein of Nav1.5, as well as INaT, remained unchanged in HF VCMs. Nav␤1-siRNA reduced INaL density and accelerated INaL two-exponential decay, whereas Nav␤2-siRNA produced an opposite effect in VCMs from both normal and failing hearts. Physiological importance of the discovered INaL modulation to affect AP shape and duration was illustrated both experimentally and by numerical simulations of a VCM excitationcontraction coupling model. We conclude that in myocytes of normal and failing dog hearts Nav␤1 and Nav␤2 exhibit oppositely directed modulation of INaL. action potential; in silico simulation THE EMERGING PARADIGM FOR Na ϩ current (I Na ) in chronic heart failure (HF) is that its transient component (I NaT ) responsible for the action potential (AP) upstroke and excitation propagation is decreased, whereas the late component (I NaL ) involved in AP plateau is augmented (21,23,25,42,45,48). Molecular mechanisms of these HF-related I Na alterations are still understudied. Numerous studies indicate a possible role of Na v ␤ auxiliary subunits to modulate Na ϩ channel (NaCh) expression and function (27), but implications of Na v ␤ in I NaL modulation have not been studied in detail, especially in HF. Our previous studies in a canine chronic HF model showed that the protein level of the main NaCh isoform expressed in the heart, Na v 1.5, underlying I NaL (18), is reduced but remains unchanged for Na v ␤ 1 -and Na v ␤ 2 -subunits, making these ␤-subunits relatively upregulated (48). Thus an intriguing possibility...

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Modulation of late sodium current by Ca²⁺, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences

Cited by 122 publications

References 50 publications

The late sodium current in heart failure: pathophysiology and clinical relevance

The late sodium current in heart failure: pathophysiology and clinical relevance

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

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Modulation of late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences

Cited by 122 publications

References 50 publications

The late sodium current in heart failure: pathophysiology and clinical relevance

The late sodium current in heart failure: pathophysiology and clinical relevance

Mechanisms of ventricular arrhythmias: a dynamical systems-based perspective

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

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Modulation of late sodium current by Ca²⁺, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences