Intercalated Disk Nanoscale Structure Regulates Cardiac Conduction

AbstractThe intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+ channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains around mechanical and gap junctions, and that perturbations of ID structure alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, the structure of the ID and intercellular cleft are not well characterized, and to date, no models have incorporated the influence of ID structure on conduction in cardiac tissue. In this study, we developed an approach to generate realistic finite element model (FEM) meshes replicating ID nanoscale structure, based on experimental measurements from transmission electron microscopy (TEM) images. We then integrated measurements of the intercellular cleft electrical conductivity, derived from the FEM meshes, into a novel cardiac tissue model formulation. FEM-based calculations predict that the distribution of cleft conductances are sensitive to regional changes in ID structure, specifically the intermembrane separation and gap junction distribution. Tissue-scale simulations demonstrated that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we find that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of post-junctional Na+ currents. Additionally, these heterogeneities lead to a weaker dependence of conduction velocity on gap junctional coupling, compared with prior modeling formulations that neglect or simplify ID structure. Further, we find that disruption of local ID nanodomains can lead to either conduction slowing or enhancing, depending on gap junctional coupling strength. Overall, our study demonstrates that ID nanoscale structure can play a significant role in regulating cardiac conduction.

Download Full-text

Intercalated disk nanoscale structure regulates cardiac conduction

The Journal of General Physiology ◽

10.1085/jgp.202112897 ◽

2021 ◽

Vol 153 (8) ◽

Author(s):

Nicolae Moise ◽

Heather L. Struckman ◽

Celine Dagher ◽

Rengasayee Veeraraghavan ◽

Seth H. Weinberg

Keyword(s):

Gap Junction ◽

Cardiac Tissue ◽

Element Model ◽

Active Role ◽

Cardiac Conduction ◽

Junctional Coupling ◽

Nanoscale Structure ◽

Gap Junctional ◽

Gap Junctional Coupling ◽

Intercalated Disk

The intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+ channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains such as the gap junction–adjacent perinexus and mechanical junction–associated adhesion-excitability nodes, and that perturbations of ID structure alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, the structures of the ID and intercellular cleft are not well characterized and, to date, no models have incorporated the influence of ID structure on conduction in cardiac tissue. In this study, we developed an approach to generate realistic finite element model (FEM) meshes replicating nanoscale of the ID structure, based on experimental measurements from transmission electron microscopy images. We then integrated measurements of the intercellular cleft electrical conductivity, derived from the FEM meshes, into a novel cardiac tissue model formulation. FEM-based calculations predict that the distribution of cleft conductances is sensitive to regional changes in ID structure, specifically the intermembrane separation and gap junction distribution. Tissue-scale simulations predict that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we found that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of postjunctional Na+ currents. Additionally, these heterogeneities lead to a weaker dependence of conduction velocity on gap junctional coupling, compared with prior modeling formulations that neglect or simplify ID structure. Further, we found that disruption of local ID nanodomains can either slow or enhance conduction, depending on gap junctional coupling strength. Our study therefore suggests that ID nanoscale structure can play a significant role in regulating cardiac conduction.

Download Full-text

The conduction velocity-potassium relationship in the heart is modulated by sodium and calcium

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-021-02537-y ◽

2021 ◽

Cited By ~ 1

Author(s):

D. Ryan King ◽

Michael Entz ◽

Grace A. Blair ◽

Ian Crandell ◽

Alexandra L. Hanlon ◽

...

Keyword(s):

Conduction Velocity ◽

Cardiac Conduction ◽

Extracellular Potassium ◽

Primary Role ◽

Junctional Coupling ◽

Severe Hyperkalemia ◽

Gap Junctional ◽

Extracellular Sodium ◽

Gap Junctional Coupling ◽

Ephaptic Coupling

Abstract The relationship between cardiac conduction velocity (CV) and extracellular potassium (K+) is biphasic, with modest hyperkalemia increasing CV and severe hyperkalemia slowing CV. Recent studies from our group suggest that elevating extracellular sodium (Na+) and calcium (Ca2+) can enhance CV by an extracellular pathway parallel to gap junctional coupling (GJC) called ephaptic coupling that can occur in the gap junction adjacent perinexus. However, it remains unknown whether these same interventions modulate CV as a function of K+. We hypothesize that Na+, Ca2+, and GJC can attenuate conduction slowing consequent to severe hyperkalemia. Elevating Ca2+ from 1.25 to 2.00 mM significantly narrowed perinexal width measured by transmission electron microscopy. Optically mapped, Langendorff-perfused guinea pig hearts perfused with increasing K+ revealed the expected biphasic CV-K+ relationship during perfusion with different Na+ and Ca2+ concentrations. Neither elevating Na+ nor Ca2+ alone consistently modulated the positive slope of CV-K+ or conduction slowing at 10-mM K+; however, combined Na+ and Ca2+ elevation significantly mitigated conduction slowing at 10-mM K+. Pharmacologic GJC inhibition with 30-μM carbenoxolone slowed CV without changing the shape of CV-K+ curves. A computational model of CV predicted that elevating Na+ and narrowing clefts between myocytes, as occur with perinexal narrowing, reduces the positive and negative slopes of the CV-K+ relationship but do not support a primary role of GJC or sodium channel conductance. These data demonstrate that combinatorial effects of Na+ and Ca2+ differentially modulate conduction during hyperkalemia, and enhancing determinants of ephaptic coupling may attenuate conduction changes in a variety of physiologic conditions.

Download Full-text

Faculty Opinions recommendation of Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1088793.541893 ◽

2007 ◽

Author(s):

Judith S Eisen

Keyword(s):

Motor Neuron ◽

Neuromuscular Synapse ◽

Synapse Elimination ◽

Neuron Firing ◽

Junctional Coupling ◽

Gap Junctional ◽

Gap Junctional Coupling

Download Full-text

Bursting in Inhibitory Interneuronal Networks: A Role for Gap-Junctional Coupling

Journal of Neurophysiology ◽

10.1152/jn.1999.81.3.1274 ◽

1999 ◽

Vol 81 (3) ◽

pp. 1274-1283 ◽

Cited By ~ 90

Author(s):

F. K. Skinner ◽

L. Zhang ◽

J. L. Perez Velazquez ◽

P. L. Carlen

Keyword(s):

Theoretical Work ◽

Oscillatory Behavior ◽

Minimal Network ◽

Junctional Coupling ◽

Synchronization Mechanisms ◽

The Individual ◽

Gap Junctional ◽

Gap Junctional Coupling ◽

Inhibitory Networks

Bursting in inhibitory interneuronal networks: a role for gap-junctional coupling. Much work now emphasizes the concept that interneuronal networks play critical roles in generating synchronized, oscillatory behavior. Experimental work has shown that functional inhibitory networks alone can produce synchronized activity, and theoretical work has demonstrated how synchrony could occur in mutually inhibitory networks. Even though gap junctions are known to exist between interneurons, their role is far from clear. We present a mechanism by which synchronized bursting can be produced in a minimal network of mutually inhibitory and gap-junctionally coupled neurons. The bursting relies on the presence of persistent sodium and slowly inactivating potassium currents in the individual neurons. Both GABAA inhibitory currents and gap-junctional coupling are required for stable bursting behavior to be obtained. Typically, the role of gap-junctional coupling is focused on synchronization mechanisms. However, these results suggest that a possible role of gap-junctional coupling may lie in the generation and stabilization of bursting oscillatory behavior.

Download Full-text

Non-ohmic tissue conduction in cardiac electrophysiology: upscaling the non-linear voltage-dependent conductance of gap junctions

10.1101/690255 ◽

2019 ◽

Author(s):

Daniel E. Hurtado ◽

Javiera Jilberto ◽

Grigory Panasenko

Keyword(s):

Computational Complexity ◽

Gap Junctions ◽

Cardiac Tissue ◽

Tissue Level ◽

Cardiac Conduction ◽

Non Linear ◽

Voltage Dependent ◽

Junctional Coupling ◽

Organ Level ◽

Electrical Propagation

AbstractGap junctions are key mediators of the intercellular communication in cardiac tissue, and their function is vital to sustain normal cardiac electrical activity. Conduction through gap junctions strongly depends on the hemichannel arrangement and transjunctional voltage, rendering the intercellular conductance highly non-Ohmic. Despite this marked non-linear behavior, current tissue-level models of cardiac conduction are rooted on the assumption that gap-junctions conductance is constant (Ohmic), which results in inaccurate predictions of electrical propagation, particularly in the low junctional-coupling regime observed under pathological conditions. In this work, we present a novel non-Ohmic multiscale (NOM) model of cardiac conduction that is suitable for tissue-level simulations. Using non-linear homogenization theory, we develop a conductivity model that seamlessly upscales the voltage-dependent conductance of gap junctions, without the need of explicitly modeling gap junctions. The NOM model allows for the simulation of electrical propagation in tissue-level cardiac domains that accurately resemble that of cell-based microscopic models for a wide range of junctional coupling scenarios, recovering key conduction features at a fraction of the computational complexity. A unique feature of the NOM model is the possibility of upscaling the response of non-symmetric gap-junction conductance distributions, which result in conduction velocities that strongly depend on the direction of propagation, thus allowing to model the normal and retrograde conduction observed in certain regions of the heart. We envision that the NOM model will enable organ-level simulations that are informed by sub- and inter-cellular mechanisms, delivering an accurate and predictive in-silico tool for understanding the heart function.Author summaryThe heart relies on the propagation of electrical impulses that are mediated gap junctions, whose conduction properties vary depending on the transjunctional voltage. Despite this non-linear feature, current mathematical models assume that cardiac tissue behaves like an Ohmic (linear) material, thus delivering inaccurate results when simulated in a computer. Here we present a novel mathematical multiscale model that explicitly includes the non-Ohmic response of gap junctions in its predictions. Our results show that the proposed model recovers important conduction features modulated by gap junctions at a fraction of the computational complexity. This contribution represents an important step towards constructing computer models of a whole heart that can predict organ-level behavior in reasonable computing times.

Download Full-text