Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias

Herren, Anthony W.; Bers, Donald M.; Grandi, Eleonora

doi:10.1152/ajpheart.00306.2013

Cited by 82 publications

(79 citation statements)

References 140 publications

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“…For normal Na channel properties in our model, subthreshold DADs failed to cause conduction block, regardless of DAD amplitude or coupling interval. However, if Na channel availability was reduced by shifting the half-maximal voltage of steady-state inactivation (described by h ∞ ) in the negative direction, as might occur physiologically with PKA, PKC or CaMKII phosphorylation of Na channels 22 or in some Brugada syndrome mutations 23 , conduction block occurred over a range of coupling intervals when DAD amplitude reached a critical range (Fig. 2B and C).…”

Section: Resultsmentioning

confidence: 98%

Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue

et al. 2015

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Background Delayed afterdepolarizations (DADs) have been well-characterized as arrhythmia triggers but their role in generating a tissue substrate vulnerable to reentry is not well understood. Objective To test the hypothesis that random DADs can self-organize to generate both an arrhythmia trigger and a vulnerable substrate simultaneously in cardiac tissue as a result of gap junction coupling. Methods Computer simulations in one-dimensional cable and two-dimensional tissue models were carried out. The cellular DAD amplitude was varied by changing the strength of sarcoplasmic reticulum Ca release. Random DAD latency and amplitude in different cells were simulated using Gaussian distributions. Results Depending on the strength of spontaneous sarcoplasmic reticulum Ca release and other conditions, random DADs in cardiac tissue resulted in the following behaviors: 1) triggered activity (TA); 2) a vulnerable tissue substrate causing unidirectional conduction block and reentry by inactivating Na channels; 3) both triggers and a vulnerable substrate simultaneously by generating TA in regions next to regions with subthreshold DADs susceptible to unidirectional conduction block and reentry. The probability of the latter two behaviors was enhanced by reduced Na channel availability, reduced gap junction coupling, increased tissue heterogeneity, and less synchronous DAD latency. Conclusions DADs can self-organize in tissue to generate arrhythmia triggers, a vulnerable tissue substrate, and both simultaneously. Reduced Na channel availability and gap junction coupling potentiate this mechanism of arrhythmias, which are relevant to a variety of heart disease conditions.

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Section: Resultsmentioning

confidence: 98%

Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue

et al. 2015

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“…Together, these observations could be a result of post-translational modification of Nav1.5 by CaMKII phosphorylation. A decrease in peak I Na may lead to conduction slowing or ventricular arrhythmias via stimulus reentry; whereas, an increase in I NaL may alter [Na + ] i or [Ca 2+ ] i homeostasis, delay repolarization, cause ventricular APD prolongation, and increase the risk of ventricular arrhythmias (215). Furthermore, CaMKII expression and activation is increased in HF, and inhibition of CaMKII is protective of HF by reducing pathological signaling and arrhythmias (12, 221, 591).…”

Section: Ventriclementioning

confidence: 99%

Ion Channels in the Heart

Bartos

Grandi

Ripplinger

2015

Comprehensive Physiology

Self Cite

164

182

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Optimal cardiac function depends on proper timing of excitation and contraction in various regions of the heart, as well as on appropriate heart rate. This is accomplished via specialized electrical properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His-Purkinje system, and ventricles. Here we review the major regionally-determined electrical properties of these cardiac regions and present the available data regarding the molecular and ionic bases of regional cardiac function and dysfunction. Understanding these differences is of fundamental importance for the investigation of arrhythmia mechanisms and pharmacotherapy.

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“…1–3 Na v 1.5 dysfunction is further linked with arrhythmias associated with acquired heart failure. 4 Based on the role of Na v 1.5 in health and disease, therapies to target select Na v 1.5 properties have remained at the forefront of cardiovascular medicine. 5 Unfortunately, the molecular pathways underlying Na v 1.5 regulation remain largely undefined partially due to lack of essential in vivo data.…”

Section: Introductionmentioning

confidence: 99%

Ankyrin-G Coordinates Intercalated Disc Signaling Platform to Regulate Cardiac Excitability In Vivo

Makara

Curran

Little

et al. 2014

Circulation Research

111

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Rationale Nav1.5 (SCN5A) is the primary cardiac voltage-gated Nav channel. Nav1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Nav1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Nav1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Nav1.5 membrane targeting, assembly, and regulation are still largely undefined. Objective Define the in vivo mechanisms underlying Nav1.5 membrane regulation. Methods and Results Here, we define the molecular basis of a Nav channel regulatory platform in heart. Using new cardiac-selective ankyrin-G−/− mice (cKO), we report that ankyrin-G targets Nav1.5, and its regulatory protein, calcium/calmodulin-dependent kinase II (CaMKII) to the intercalated disc. Mechanistically, βIV-spectrin is requisite for ankyrin-dependent targeting of CaMKIIδ, however βIV-spectrin is not essential for ankyrin-G expression. Ankyrin-G cKO myocytes display decreased Nav1.5 expression/membrane localization, and reduced INa associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Nav channel antagonists. Moreover, we report that ankyrin-G links Nav channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to beta-adrenergic stimulation. Conclusions Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Nav1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Nav1.5.

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Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias

Cited by 82 publications

References 140 publications

Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue

Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue

Ion Channels in the Heart

Ankyrin-G Coordinates Intercalated Disc Signaling Platform to Regulate Cardiac Excitability In Vivo

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