Cardiac electrophysiology models are among the most mature and well-studied mathematical models of biological systems. This maturity is bringing new challenges as models are being used increasingly to make quantitative rather than qualitative predictions. As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model. This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology. We discuss the classic and latest approaches to calibration in the electrophysiology field, at both the ion channel and cellular AP scales. We end with a discussion of the many challenges that work to date has raised and the need for reproducible descriptions of the calibration process to enable models to be recalibrated to new data sets and built upon for new studies. This article is categorized under: Analytical and Computational Methods > Computational Methods Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Cellular Models.

Calibration of ionic and cellular cardiac electrophysiology models.

The development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete compartments. Four types of intercellular junction are present in vertebrates: desmosomes, adherens junctions, tight junctions, and gap junctions. All are essential for the development of the embryonic layers and organs as well as adult tissue homeostasis. While each junction type is defined as a distinct entity, it is now clear that they cooperate physically and functionally to create a robust and functionally diverse system. During evolution, desmosomes first appeared in vertebrates as highly specialized regions at the plasma membrane that couple the intermediate filament cytoskeleton at points of strong cell–cell adhesion. Here, we review how desmosomes conferred new mechanical and signaling properties to vertebrate cells and tissues through their interactions with the existing junctional and cytoskeletal network.

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Desmosomes: Essential contributors to an integrated intercellular junction network

We investigated targeting mechanisms of Na+ and KATP channels to the intercalated disk (ICD) of cardiomyocytes. Patch clamp and surface biotinylation data show reciprocal downregulation of each other's surface density. Mutagenesis of the Kir6.2 ankyrin binding site disrupts this functional coupling. Duplex patch clamping and Angle SICM recordings show that INa and IKATP functionally co-localize at the rat ICD, but not at the lateral membrane. Quantitative STORM imaging show that Na+ and KATP channels are localized close to each other and to AnkG, but not to AnkB, at the ICD. Peptides corresponding to Nav1.5 and Kir6.2 ankyrin binding sites dysregulate targeting of both Na+ and KATP channels to the ICD, but not to lateral membranes. Finally, a clinically relevant gene variant that disrupts KATP channel trafficking also regulates Na+ channel surface expression. The functional coupling between these two channels need to be considered when assessing clinical variants and therapeutics.

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Ankyrin-G mediates targeting of both Na+ and KATP channels to the rat cardiac intercalated disc

Background: Rapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT...

Balance Between Rapid Delayed Rectifier K+ Current and Late Na+ Current on Ventricular Repolarization: An Effective Antiarrhythmic Target?

Cardiac voltage-gated sodium channel NaV1.5, encoded by SCN5A, is crucial for the upstroke of action potential and excitation of cardiomyocytes. NaV1.5 undergoes complex processes before it reaches the target membrane microdomains and performs normal functions. A variety of protein partners are needed to achieve the balance between SCN5A transcription and mRNA decay, endoplasmic reticulum retention and export, Golgi apparatus retention and export, selective anchoring and degradation, activation, and inactivation of sodium currents. Subtle alterations can impair NaV1.5 in terms of expression or function, eventually leading to NaV1.5-associated diseases such as lethal arrhythmias and cardiomyopathy.

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Life Cycle of the Cardiac Voltage-Gated Sodium Channel NaV1.5.

Catastrophic arrhythmias and sudden cardiac death can occur with even a small imbalance between inward sodium currents and outward potassium currents, but mechanisms establishing this critical balance are not understood. Here, we show that mRNA transcripts encoding INa and IKr channels (SCN5A and hERG, respectively) are associated in defined complexes during protein translation. Using biochemical, electrophysiological and single-molecule fluorescence localization approaches, we find that roughly half the hERG translational complexes contain SCN5A transcripts. Moreover, the transcripts are regulated in a way that alters functional expression of both channels at the membrane. Association and coordinate regulation of transcripts in discrete 'microtranslatomes' represents a new paradigm controlling electrical activity in heart and other excitable tissues.

A microtranslatome coordinately regulates sodium and potassium currents in the human heart.

Activation of the electrical signal and its transmission as a depolarizing wave in the whole heart requires highly organized myocyte architecture and cell-cell contacts In addition, complex trafficking and anchoring intracellular machineries regulate the proper surface expression of channels and their targeting to distinct membrane domains An increasing list of proteins, lipids, and second messengers can contribute to the normal targeting of ion channels in cardiac myocytes However, their precise roles in the electrophysiology of the heart are far from been extensively understood Nowadays, much effort in the field focuses on understanding the mechanisms that regulate ion channel targeting to sarcolemma microdomains and their organization into macromolecular complexes The purpose of the present section is to provide an overview of the characterized partners of the main cardiac sodium channel, NaV15, involved in regulating the functional expression of this channel both in terms of trafficking and targeting into microdomains

The Cardiac Sodium Channel and Its Protein Partners.

A stable cell line inducibly expressing hERG1a/1b heteromeric channels.

Catastrophic arrhythmias and sudden cardiac death can occur with even a small imbalance between inward sodium currents and outward potassium currents, but mechanisms establishing this critical balance are not understood. Here, we show that mRNA transcripts encoding INa and IKr channels (SCN5A and hERG, respectively) are associated in defined complexes during protein translation. Using biochemical, electrophysiological and single-molecule fluorescence localization approaches, we find that roughly half the hERG translational complexes contain SCN5A transcripts. Moreover, the transcripts are regulated in a way that alters functional expression of both channels at the membrane. Association and coordinate regulation of transcripts in discrete “microtranslatomes” represents a new paradigm controlling electrical activity in heart and other excitable tissues.

/pdf/a-microtranslatome-coordinately-regulates-sodium-and-lo1zpbkg0t.pdf

Catherine A. Eichel

Papers

A microtranslatome coordinately regulates sodium and potassium currents in the human heart.

The Cardiac Sodium Channel and Its Protein Partners.

A stable cell line inducibly expressing hERG1a/1b heteromeric channels.

A microtranslatome coordinately regulates sodium and potassium currents in the heart