Modulatory Effect of the Transcellular Electrical Field on Gap Junction Conductance

Anisotropy can lead to unidirectional conduction block that initiates reentry. We analyzed the mechanisms in patterned anisotropic neonatal rat ventricular myocyte monolayers. Voltage and intracellular Ca (Cai) were optically mapped under the following conditions: extrastimulus (S1S2) testing and/or tetrodotoxin (TTX) to suppress Na current availability; heptanol to reduce gap junction conductance; and incremental rapid pacing. In anisotropic monolayers paced at 2 Hz, conduction velocity (CV) was faster longitudinally than transversely, with an anisotropy ratio [AR = CVL/CVT, where CVL and CVT are CV in the longitudinal and transverse directions, respectively], averaging 2.1 ± 0.8. Interventions decreasing Na current availability, such as S1S2 pacing and TTX, slowed CVL and CVT proportionately, without changing the AR. Conduction block preferentially occurred longitudinal to fiber direction, commonly initiating reentry. Interventions that decreased gap junction conductance, such as heptanol, decreased CVT more than CVL, increasing the AR and causing preferential transverse conduction block and reentry. Rapid pacing resembled the latter, increasing the AR and promoting transverse conduction block and reentry, which was prevented by the Cai chelator 1,2-bis oaminophenoxy ethane- N, N, N′, N′-tetraacetic acid (BAPTA). In contrast to isotropic and uniformly anisotropic monolayers, in which reentrant rotors drifted and self-terminated, bidirectional anisotropy (i.e., an abrupt change in fiber direction exceeding 45°) caused reentry to anchor near the zone of fiber direction change in 77% of monolayers. In anisotropic monolayers, unidirectional conduction block initiating reentry can occur longitudinal or transverse to fiber direction, depending on whether the experimental intervention reduces Na current availability or decreases gap junction conductance, agreeing with theoretical predictions.

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Protein Kinase Cα Mediates the Effect of Antiarrhythmic Peptide on Gap Junction Conductance

Cell Communication & Adhesion ◽

10.3109/15419060109080734 ◽

2001 ◽

Vol 8 (4-6) ◽

pp. 257-264 ◽

Cited By ~ 21

Author(s):

Stefan Dhein ◽

Stephan Weng ◽

Rajiv Grover ◽

Tatjana Tudyka ◽

Michaela Gottwald ◽

...

Keyword(s):

Protein Kinase ◽

Gap Junction ◽

Antiarrhythmic Peptide ◽

Protein Kinase Cα ◽

Junction Conductance

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Opposing modulation of Cx26 gap junctions and hemichannels by CO2

10.1101/584722 ◽

2019 ◽

Cited By ~ 3

Author(s):

Sarbjit Nijjar ◽

Daniel Maddison ◽

Louise Meigh ◽

Elizabeth de Wolf ◽

Thomas Rodgers ◽

...

Keyword(s):

Gap Junctions ◽

Gap Junction ◽

Intracellular Acidification ◽

Dye Transfer ◽

Network Modelling ◽

Elastic Network ◽

Median Reduction ◽

Whole Cell Recordings ◽

Junction Conductance ◽

Glucose Analogue

SummaryCx26 hemichannels open in response to moderate elevations of CO2 (PCO2 55 mmHg) via a carbamylation reaction that depends on residues K125 and R104. Here we investigate the action of CO2 on Cx26 gap junctions. Using a dye transfer assay, we found that an elevated PCO2 of 55 mmHg greatly delayed the permeation of a fluorescent glucose analogue (NBDG) between HeLa cells coupled by Cx26 gap junctions. However, the mutations K125R or R104A abolished this effect of CO2. Whole cell recordings demonstrated that elevated CO2 reduced the Cx26 gap junction conductance (median reduction 5.6 nS, 95% confidence interval, 3.2 to 11.9 nS) but had no effect on Cx26K125R or Cx31 gap junctions. CO2 can cause intracellular acidification, but using 30 mM propionate we found that acidification in the absence of a change in PCO2 caused a median reduction in the gap junction conductance of 5.3 nS (2.8 to 8.3 nS). This effect of propionate was unaffected by the K125R mutation (median reduction 7.7 nS, 4.1 to 11.0 nS). pH-dependent and CO2-dependent closure of the gap junction are thus mechanistically independent. Mutations of Cx26 associated with the Keratitis Ichthyosis Deafness syndrome (N14K, A40V and A88V) also abolished the CO2-dependent gap junction closure. Elastic network modelling suggests that the lowest entropy state when CO2 is bound, is the closed configuration for the gap junction but the open state for the hemichannel. The opposing actions of CO2 on Cx26 gap junctions and hemichannels thus depend on the same residues and presumed carbamylation reaction.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00493.2011 ◽

2012 ◽

Vol 302 (4) ◽

pp. H934-H952 ◽

Cited By ~ 14

Author(s):

Polina S. Petkova-Kirova ◽

Barry London ◽

Guy Salama ◽

Randall L. Rasmusson ◽

Vladimir E. Bondarenko

Keyword(s):

Heart Failure ◽

Gap Junction ◽

Ventricular Myocytes ◽

Mouse Heart ◽

Intercellular Coupling ◽

Human Heart Failure ◽

Tnf Α ◽

Cycle Lengths ◽

Factor Α ◽

Junction Conductance

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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Conduction block in Purkinje fibers by homogeneous versus localized decrease of the gap junction conductance

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-070 ◽

1998 ◽

Vol 76 (6) ◽

pp. 630-641

Author(s):

Pascal Daleau ◽

Jean Délèze

Keyword(s):

Action Potential ◽

Gap Junction ◽

Sodium Current ◽

Resistivity Measurement ◽

Conduction Block ◽

Central Compartment ◽

Internal Resistance ◽

The Core ◽

Junction Conductance ◽

Core Conductor

Gap junction channels provide the pathway for the cell-to-cell propagation of cardiac action potential.Impairment of junctional conductance decreases conduction velocity and can cause block, two conditions that favorventricular arrhythmias and fibrillation by re-entrant excitation. These experiments were designed to examine theeffects of homogeneous versus localized decrease of the gap junction conductance on propagation of action potential inPurkinje fibers from sheep hearts. The fibers were mounted in a three-compartment chamber, and cell-to-cellconductance was progressively reduced by applying heptanol either over a central 2-mm segment or over the wholefiber length. The internal resistivities (Ri ) at which conduction of the action potential became blocked were determinedin both cases. With 3.5 mM heptanol in the central compartment, conduction failed when Ri was increased by only34.6 times the control values. In contrast, when the same concentration of heptanol was added simultaneously to allthree compartments, Ri had to rise by a factor of 7.59.4 before conduction became decremental and was blocked. Inboth situations, dV/dtmax at the time of conduction block was similarly decreased to about 50% of the control values.Other parameters being equal, a moderate decrease of the gap junction conductance and of the fast sodium current,insufficient to block propagation of the action potential when they are homogeneously distributed, become sufficient tointerrupt conduction if the action potential merges abruptly into a portion of fiber with normal internal conductivity atthe outlet of the area of increased resistance. This greater sensitivity to block is accounted for by the increase inelectrical load at the discontinuity in the core conductor between the region of increased internal resistance and thenormal part of fiber that follows. Areas of steep transition from high to low input resistances of the core conductor,such as may develop in localized ischemia, therefore appear particularly susceptible to conduction failure.Key words: electrical uncoupling, internal resistivity measurement, discontinuous internal resistance, arrhythmia, sheep heart.

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Regional gap junction inhibition increases defibrillation thresholds

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01074.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. H10-H16 ◽

Cited By ~ 12

Author(s):

J. Jason Sims ◽

Kell L. Schoff ◽

Jennifer M. Loeb ◽

Nicholas A. Wiegert

Keyword(s):

Ventricular Fibrillation ◽

Gap Junction ◽

Conduction Velocity ◽

Velocity Dispersion ◽

Important Determinant ◽

Refractory Periods ◽

Regional Gap ◽

Junction Conductance ◽

Regional Infusion ◽

Gap Junction Inhibition

It is clear that ischemia inhibits successful defibrillation by altering regional electro-physiology. However, the exact mechanisms are unclear. This study investigated whether regional gap junction inhibition increases biphasic shock defibrillation thresholds (DFT). Sixteen swine were instrumented with a mid-left anterior descending (LAD) perfusion catheter for regional infusion of 0.5 mM/h heptanol ( n = 8) or saline ( n = 8). DFT values and effective refractory periods (ERP) at five myocardial sites were determined. Regional conduction velocity (CV) was determined in an LAD drug-perfused and nondrug-perfused region in an additional seven swine. Regional heptanol infusion increased 50% DFT values by 33% ( P = 0.01) and slowed CV by 42–59% ( P < 0.01) but did not affect ERP. Regional heptanol also increased CV dispersion by ∼270% ( P < 0.05) but did not change ERP dispersion. Regional placebo did not alter any of these parameters. Furthermore, regional heptanol infusion induced spontaneous ventricular fibrillation in eight of eight animals. Increasing spatial conduction velocity dispersion by impairing regional gap junction conductance increased DFT values. Dispersion in conduction velocity slowing during regional ischemia may be an important determinant of defibrillation efficacy.

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The Effect of Gap Junction Conductance on Synchronisation of Sinoatrial Node Central Cells

10.1063/1.3596637 ◽

2011 ◽

Author(s):

Sittisede Polwiang ◽

Adelle C. F. Coster ◽

Tuan D. Pham ◽

Xiaobo Zhou ◽

Hiroshi Tanaka ◽

...

Keyword(s):

Gap Junction ◽

Sinoatrial Node ◽

Junction Conductance

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