Neuronal Na+ Channels Are Integral Components of Pro-Arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-Adrenergic Stimulation

Radwański, Przemysław; Ho, Hsiang‐Ting; Veeraraghavan, Rengasayee; Brunello, Lucia; Liu, Bin; Belevych, Andriy E.; Unudurthi, Sathya D.; Makara, Michael; Priori, Silvia G.; Volpe, Pompeo; Armoundas, Antonis A.; Dillmann, Wolfgang H.; Knollmann, Björn C.; Mohler, Peter J.; Hund, Thomas J.; Györke, Sándor

doi:10.1016/j.jacbts.2016.04.004

Cited by 33 publications

(85 citation statements)

References 69 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As another interesting possibility, we recently showed that local Na + /Ca 2+ signaling involving neuronal Na + channel plays an important role in the genesis of Ca 2+ -dependent arrhythmia [34]. Stimulation of neuronal Na + channels by CaMK∏ results in increased Na + influx and hence increased Ca 2+ level in the junctional space.…”

Section: Discussionmentioning

confidence: 99%

The role of spatial organization of Ca2+ release sites in the generation of arrhythmogenic diastolic Ca2+ release in myocytes from failing hearts

Belevych

Bonilla

et al. 2017

Basic Res Cardiol

Self Cite

View full text Add to dashboard Cite

In heart failure (HF), dysregulated cardiac ryanodine receptors (RyR2) contribute to the generation of diastolic Ca2+ waves (DCWs), thereby predisposing adrenergically stressed failing hearts to life-threatening arrhythmias. However, the specific cellular, subcellular, and molecular defects that account for cardiac arrhythmia in HF remain to be elucidated. Patch-clamp techniques and confocal Ca2+ imaging were applied to study spatially defined Ca2+ handling in ventricular myocytes isolated from normal (control) and failing canine hearts. Based on their activation time upon electrical stimulation, Ca2+ release sites were categorized as coupled, located in close proximity to the sarcolemmal Ca2+ channels, and uncoupled, the Ca2+ channel-free non-junctional Ca2+ release units. In control myocytes, stimulation of β-adrenergic receptors with isoproterenol (Iso) resulted in a preferential increase in Ca2+ spark rate at uncoupled sites. This site-specific effect of Iso was eliminated by the phosphatase inhibitor okadaic acid, which caused similar facilitation of Ca2+ sparks at coupled and uncoupled sites. Iso-challenged HF myocytes exhibited increased predisposition to DCWs compared to control myocytes. In addition, the overall frequency of Ca2+ sparks was increased in HF cells due to preferential stimulation of coupled sites. Furthermore, coupled sites exhibited accelerated recovery from functional refractoriness in HF myocytes compared to control myocytes. Spatially resolved subcellular Ca2+ mapping revealed that DCWs predominantly originated from coupled sites. Inhibition of CaMK∏ suppressed DCWs and prevented preferential stimulation of coupled sites in Iso-challenged HF myocytes. These results suggest that CaMK∏-(and phosphatase)-dependent dysregulation of junctional Ca2+ release sites contributes to Ca2+-dependent arrhythmogenesis in HF.

show abstract

Section: Discussionmentioning

confidence: 99%

The role of spatial organization of Ca2+ release sites in the generation of arrhythmogenic diastolic Ca2+ release in myocytes from failing hearts

Belevych

Bonilla

et al. 2017

Basic Res Cardiol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Adapted from Radwański et al . (). C , higher magnification views of regions from A showing two possible scenarios of nNa V localization within t‐tubules.…”

Section: The Interplay Between Sodium and Calciummentioning

confidence: 97%

“…; Radwański et al . ). Notably, PLA signal is only generated when colabelled proteins are within ∼40 nm of each other (Gullberg & Andersson, ) suggesting very close association between nNa V s and Ca 2+ cycling proteins (Fig.…”

Section: The Interplay Between Sodium and Calciummentioning

confidence: 97%

“…A , bottom panel) (Radwański et al . ). The notion of CaMKII regulation of Na + influx is consistent with work in genetic models where CaMKII is either rendered constitutively active (Wagner et al .…”

Section: The Interplay Between Sodium and Calciummentioning

confidence: 97%

“…However, in a setting of altered RyR2 function, augmentation of nNa V activity may in fact be proarrhythmic (Radwański et al . ).…”

Section: The Interplay Between Sodium and Calciummentioning

confidence: 97%

See 2 more Smart Citations

Neuronal sodium channels: emerging components of the nano‐machinery of cardiac calcium cycling

Veeraraghavan

Györke

Radwański

2017

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Excitation-contraction coupling is the bridge between cardiac electrical activation and mechanical contraction. It is driven by the influx of Ca across the sarcolemma triggering Ca release from the sarcoplasmic reticulum (SR) - a process termed Ca -induced Ca release (CICR) - followed by re-sequestration of Ca into the SR. The Na /Ca exchanger inextricably couples the cycling of Ca and Na in cardiac myocytes. Thus, influx of Na via voltage-gated Na channels (Na ) has emerged as an important regulator of CICR both in health and in disease. Recent insights into the subcellular distribution of cardiac and neuronal Na isoforms and their ultrastructural milieu have important implications for the roles of these channels in mediating Ca -driven arrhythmias. This review will discuss functional insights into the role of neuronal Na isoforms vis-à-vis cardiac Na s in triggering such arrhythmias and their potential as therapeutic targets in the context of the aforementioned structural observations.

show abstract

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Chen

Wang

et al. 2021

Clinical & Translational Med

View full text Add to dashboard Cite

Cardiac voltage‐gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC‐related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life‐threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart‐related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well‐studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.

show abstract

Neuronal Na+ Channels Are Integral Components of Pro-Arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-Adrenergic Stimulation

Cited by 33 publications

References 69 publications

The role of spatial organization of Ca2+ release sites in the generation of arrhythmogenic diastolic Ca2+ release in myocytes from failing hearts

The role of spatial organization of Ca2+ release sites in the generation of arrhythmogenic diastolic Ca2+ release in myocytes from failing hearts

Neuronal sodium channels: emerging components of the nano‐machinery of cardiac calcium cycling

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Contact Info

Product

Resources

About