Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca++.

White, Roy L.; Doeller, Jeannette E.; Verselis, Vytas K.; Wittenberg, Beatrice A.

doi:10.1085/jgp.95.6.1061

Cited by 135 publications

(72 citation statements)

References 23 publications

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“…This is why Ca 2ϩ alternans does not significantly affect the vulnerable window for reentry. We do not exclude though that impaired Ca 2ϩ handling could contribute to reducing g gap , since internal Ca 2ϩ has been shown to have an effect on this parameter (66).…”

Section: Differences In Aps and Ca 2ϩ Handling In Isolated Ventriculamentioning

confidence: 95%

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Petkova-Kirova

London

Salama

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca2+ handling, arrhythmias, and decreased survival. Although TNF-α mice have been studied extensively with a number of experimental methods, the mechanisms of heart failure are not completely understood. We created a mathematical model that reproduced experimentally observed changes in the action potential (AP) and Ca2+ handling of isolated TNF-α mice ventricular myocytes. To study the contribution of the differences in ion currents, AP, Ca2+ handling, and intercellular coupling to the development of arrhythmias in TNF-α mice, we further created several multicellular model tissues with combinations of wild-type (WT)/reduced gap junction conductance, WT/prolonged AP, and WT/decreased Na+ current ( INa) amplitude. All model tissues were examined for susceptibility to Ca2+ alternans, AP propagation block, and reentry. Our modeling results demonstrated that, similar to experimental data in TNF-α mice, Ca2+ alternans in TNF-α tissues developed at longer basic cycle lengths. The greater susceptibility to Ca2+ alternans was attributed to the prolonged AP, resulting in larger inactivation of INa, and to the decreased SR Ca2+ uptake and corresponding smaller SR Ca2+ load. Simulations demonstrated that AP prolongation induces an increased susceptibility to AP propagation block. Programmed stimulation of the model tissues with a premature impulse showed that reduced gap junction conduction increased the vulnerable window for initiation reentry, supporting the idea that reduced intercellular coupling is the major factor for reentrant arrhythmias in TNF-α mice.

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Section: Differences In Aps and Ca 2ϩ Handling In Isolated Ventriculamentioning

confidence: 95%

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Petkova-Kirova

London

Salama

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…The unique subcellular localization of NHE1 in certain cell types suggests that NHE1 has additional biological functions to those outlined above. In cardiac myocytes, the specific localization of NHE1 to intercalated disks and T-tubules, but not to peripheral sarcolemmal membranes, is thought to induce pH microdomains affecting the activity of pH-sensitive proteins, such as the gap-junction protein connexin 43 [174] and the ryanodine-sensitive Ca ++ release channel [183].…”

Section: Slc9a1-nhe1mentioning

confidence: 99%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

141

122

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The SLC9 gene family encodes Na + /H + exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

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“…Increasing concentration of intracellular calcium ion, reduced pH, and the loss of ATP is considered to be the main stimuli to cause acute reduction in gap junction conductance during ischaemia [36,82]. After the onset of ischaemia a progressive increase in intracellular calcium concentration and decrease in pH can be observed.…”

Section: Modulation Of Gap Junction Channel Functionmentioning

confidence: 99%

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Magyar

Bányász

Szentandrássy

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca++.

Cited by 135 publications

References 23 publications

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

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