Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc

Leo‐Macias, Alejandra; Agullo‐Pascual, Esperanza; Sanchez-Alonso, Jose L.; Keegan, Sarah; Lin, Xianming; Arcos, Tatiana; Feng-Xia-Liang,; Korchev, Yuri; Gorelik, Julia; Fenyö, David; Rothenberg, Eli; Delmar, Mario

doi:10.1038/ncomms10342

Cited by 86 publications

(98 citation statements)

References 66 publications

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“…Because smaller Na V 1.5 clusters have been linked to reduced functionality, the observed decreased cluster size at the LM of failing myocytes readily explains the reduction in I Na measured within this region 28. The reduction in I Na amplitude recorded at the LM using the macropatch method was larger than the observed reduction in whole cell current density.…”

Section: Discussionmentioning

confidence: 78%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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BackgroundCardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region‐specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure.Methods and ResultsMice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham–operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole‐cell sodium current (INa) density was decreased by 30% in TAC versus sham–operated on cardiomyocytes. On macropatch analysis, INa in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter‐]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z‐groove ratios). Using scanning ion conductance microscopy, cell‐attached recordings in LM subdomains revealed decreased INa and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α‐tubulin and Glu‐tubulin expression). Superresolution microscopy showed reduced average NaV1.5 cluster size at the LM of TAC cells, in line with reduced INa.ConclusionsHeart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in NaV1.5 clustering and INa within distinct subcellular microdomains of failing cardiomyocytes.

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Section: Discussionmentioning

confidence: 78%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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“…; Leo‐Macias et al . ). A high density of Na + channels was also observed at intercellular contacts in cardiomyocyte cultures (Kucera et al .…”

Section: Introductionmentioning

confidence: 97%

“…; Leo‐Macias et al . ), where, according to most recent estimations, about 50% of Na + channels are located (Lin et al . ; Shy et al .…”

Section: Introductionmentioning

confidence: 99%

Distribution of cardiac sodium channels in clusters potentiates ephaptic interactions in the intercalated disc

Hichri

Abriel

Kučera

2018

The Journal of Physiology

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It has been proposed that ephaptic interactions in intercalated discs, mediated by extracellular potentials, contribute to cardiac impulse propagation when gap junctional coupling is reduced. However, experiments demonstrating ephaptic effects on the cardiac Na current (I ) are scarce. Furthermore, Na channels form clusters around gap junction plaques, but the electrophysiological significance of these clusters has never been investigated. In patch clamp experiments with HEK cells stably expressing human Na 1.5 channels, we examined how restricting the extracellular space modulates I elicited by an activation protocol. In parallel, we developed a high-resolution computer model of the intercalated disc to investigate how the distribution of Na channels influences ephaptic interactions. Approaching the HEK cells to a non-conducting obstacle always increased peak I at step potentials near the threshold of I activation and decreased peak I at step potentials far above threshold (7 cells, P = 0.0156, Wilcoxon signed rank test). These effects were consistent with corresponding control simulations with a uniform Na channel distribution. In the intercalated disc computer model, redistributing the Na channels into a central cluster of the disc potentiated ephaptic effects. Moreover, ephaptic impulse transmission from one cell to another was facilitated by clusters of Na channels facing each other across the intercellular cleft when gap junctional coupling was reduced. In conclusion, our proof-of-principle experiments demonstrate that confining the extracellular space modulates cardiac I , and our simulations reveal the functional role of the aggregation of Na channels in the perinexus. These findings highlight novel concepts in the physiology of cardiac excitation.

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“…Recently, we and others demonstrated that Nav1.5 8–13 and Na + current 14, 15 are enhanced in the intercalated disk (ID). Further, we suggested that the narrow intercellular separation in Nav1.5 rich nanodomains could modulate electrical coupling via localized extracellular ion-mediated effects, also termed ephaptic coupling (EpC) 10, 16–18 .…”

Section: Introductionmentioning

confidence: 99%

Revealing the Concealed Nature of Long-QT Type 3 Syndrome

Greer-Short

George

Poelzing

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction due to reduced sodium current driving force, termed “self-attenuation.” We tested the novel hypothesis that self-attenuation can “mask” the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs). Methods and Results Acute interstitial edema (AIE) was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, AIE exacerbated action potential duration prolongation and produced EADs, in particular at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, while for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs. Conclusions We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.

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Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc

Cited by 86 publications

References 66 publications

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Distribution of cardiac sodium channels in clusters potentiates ephaptic interactions in the intercalated disc

Revealing the Concealed Nature of Long-QT Type 3 Syndrome

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