Na microdomains and sparks: Role in cardiac excitation-contraction coupling and arrhythmias in ankyrin-B deficiency.

07:00 EST 4th February 2019 | BioPortfolio

Summary of "Na microdomains and sparks: Role in cardiac excitation-contraction coupling and arrhythmias in ankyrin-B deficiency."

Cardiac sodium (Na) potassium ATPase (NaK) pumps, neuronal sodium channels (I), and sodium calcium (Ca) exchangers (NCX1) may co-localize to form a Na microdomain. It remains controversial as to whether neuronal I contributes to local Na accumulation, resulting in reversal of nearby NCX1 and influx of Ca into the cell. Therefore, there has been great interest in the possible roles of a Na microdomain in cardiac Ca-induced Ca release (CICR). In addition, the important role of co-localization of NaK and NCX1 in regulating localized Na and Ca levels and CICR in ankyrin-B deficient (ankyrin-B) cardiomyocytes has been examined in many recent studies. Altered Na dynamics may contribute to the appearance of arrhythmias, but the mechanisms underlying this relationship remain unclear. In order to investigate this, we present a mechanistic canine cardiomyocyte model which reproduces independent local dyadic junctional SR (JSR) Ca release events underlying cell-wide excitation-contraction coupling, as well as a three-dimensional super-resolution model of the Ca spark that describes local Na dynamics as governed by NaK pumps, neuronal I, and NCX1. The model predicts the existence of Na sparks, which are generated by NCX1 and exhibit significantly slower dynamics as compared to Ca sparks. Moreover, whole-cell simulations indicate that neuronal I in the cardiac dyad plays a key role during the systolic phase. Rapid inward neuronal I can elevate dyadic [Na] to 35-40 mM, which drives reverse-mode NCX1 transport, and therefore promotes Ca entry into the dyad, enhancing the trigger for JSR Ca release. The specific role of decreased co-localization of NaK and NCX1 in ankyrin-B cardiomyocytes was examined. Model results demonstrate that a reduction in the local NCX1- and NaK-mediated regulation of dyadic [Ca] and [Na] results in an increase in Ca spark activity during isoproterenol stimulation, which in turn stochastically activates NCX1 in the dyad. This alteration in NCX1/NaK co-localization interrupts the balance between NCX1 and NaK currents in a way that leads to enhanced depolarizing inward current during the action potential plateau, which ultimately leads to a higher probability of L-type Ca channel reopening and arrhythmogenic early-afterdepolarizations.


Journal Details

This article was published in the following journal.

Name: Journal of molecular and cellular cardiology
ISSN: 1095-8584


DeepDyve research library

PubMed Articles [14838 Associated PubMed Articles listed on BioPortfolio]

CaMKII signaling in heart diseases: Emerging role in diabetic cardiomyopathy.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is upregulated in diabetes and significantly contributes to cardiac remodeling with increased risk of cardiac arrhythmias. Diabetes is frequentl...

Interpolated Purkinje potentials recorded at a successful ablation site of a fascicular premature ventricular contraction during sinus rhythm.

The inhibitory subunit of cardiac troponin (cTnI) is modified by arginine methylation in the human heart.

The inhibitory subunit of cardiac troponin (cTnI) is a gold standard cardiac biomarker and also an essential protein in cardiomyocyte excitation-contraction coupling. The interactions of cTnI with oth...

Ryanodine receptor dispersion disrupts Ca release in failing cardiac myocytes.

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganiza...

Mechanisms of cardiac ethanol toxicity and novel treatment options.

Ethanol can acutely and chronically alter cardiomyocyte and whole-organ function in the heart. Importantly, ethanol acutely and chronically predisposes to arrhythmias, while chronic abuse can induce h...

Clinical Trials [5914 Associated Clinical Trials listed on BioPortfolio]

Role of Amino Acids and Genetic Disorder in Pathogenesis of Heart Failure

Heart failure (HF) is a continuously growing public health problem. The study aim to provide novel insights into the role of amino acids in pathogenesis of heart failure, to obtain a bette...

Magnesium Supplementation for the Prevention of Supraventricular Arrhythmias

The primary objective of this research is to determine whether oral magnesium supplementation in healthy, community-living individuals will be associated with reductions in the burden of a...

Ventriculo-arterial Coupling Modification Evaluated by PRAM During TAVI Procedure

Calcified aortic stenosis is the most frequent valvulopathy in Europe and North America. Aortic stenosis is an obstacle to the ejection of blood from the left ventricle to the aorta and le...

ARrhythmias in MYocarditis

Myocarditis promotes the occurrence of serious cardiac arrhythmias and conduction disorders which may lead to sudden cardiac death, the need for catheter ablation of arrhythmia or implanta...

Cardiac Allograft Vasculopathy and Dobutamine Stress Echocardiography / Brain Natriuretic Peptide Coupling

Primary purpose :To early detect cardiac allograft vasculopathy and to identify patients with high risk of cardiac events, by coupling the analysis of the kinetics of the brain natriuretic...

Medical and Biotech [MESH] Definitions

A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.

Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.

A process fundamental to muscle physiology whereby an electrical stimulus or action potential triggers a myocyte to depolarize and contract. This mechanical muscle contraction response is regulated by entry of calcium ions into the cell.

Coronary vasodilator; inhibits calcium function in muscle cells in excitation-contraction coupling; proposed as antiarrhythmic and antianginal agents.

Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants.

Quick Search


DeepDyve research library

Relevant Topic

Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Searches Linking to this Article