Role of asymmetry and external noise in the development and synchronization of oscillations in the analog Hopfield neural networks with time delay.

The analog Hopfield neural network with time delay and random connections has been studied for its similarities in activity to human electroencephalogram and its usefulness in other areas of the applied sciences such as speech recognition, image analysis, and electrocardiogram modeling. Our goal here is to understand the mechanisms that affect the rhythmic activity in the neural network and how the addition of a Gaussian noise contributes to the network behavior. The neural network studied is composed of ten identical neurons.

Caveolae-associated cAMP/Ca-mediated mechano-chemical signal transduction in mouse atrial myocytes.

Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca signaling in atrial cardiomyocytes.

A compartmentalized mathematical model of the β- and β-adrenergic signaling systems in ventricular myocytes from mouse in heart failure.

Mouse models of heart failure are extensively used to research human cardiovascular diseases. In particular, one of the most common is the mouse model of heart failure resulting from transverse aortic constriction (TAC). Despite this, there are no comprehensive compartmentalized mathematical models that describe the complex behavior of the action potential, [Ca] transients, and their regulation by β- and β-adrenergic signaling systems in failing mouse myocytes.

A compartmentalized mathematical model of mouse atrial myocytes.

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca] transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca] dynamics, and β-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system.

Mathematical model for β-adrenergic regulation of the mouse ventricular myocyte contraction.

The β-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the β-adrenergic signaling system can lead to cardiac hypertrophy and heart failure.

A Mathematical Model of the Human Cardiac Na Channel.

Sodium ion channel is a membrane protein that plays an important role in excitable cells, as it is responsible for the initiation of action potentials. Understanding the electrical characteristics of sodium channels is essential in predicting their behavior under different physiological conditions. We investigated several Markov models for the human cardiac sodium channel Na1.

Mathematical modeling physiological effects of the overexpression of β-adrenoceptors in mouse ventricular myocytes.

Transgenic (TG) mice overexpressing β-adrenergic receptors (β-ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing β-ARs. We found that most of the β-ARs are active in control conditions in TG mice.

Bursting dynamics in the normal and failing hearts.

A failing heart differs from healthy hearts by an array of symptomatic characteristics, including impaired Ca transients, upregulation of Na/Ca exchanger function, reduction of Ca uptake to sarcoplasmic reticulum, reduced K currents, and increased propensity to arrhythmias. While significant efforts have been made in both experimental studies and model development to display the causes of heart failure, the full process of deterioration from a healthy to a failing heart yet remains deficiently understood. In this paper, we analyze a highly detailed mathematical model of mouse ventricular myocytes to disclose the key mechanisms underlying the continual transition towards a state of heart failure.

Distinct physiological effects of β- and β-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model.

The β- and β-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data show that the activation of the β-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, whereas the effects of the β-adrenergic signaling system is less apparent. In this paper, a comprehensive compartmentalized experimentally based mathematical model of the combined β- and β-adrenergic signaling systems in mouse ventricular myocytes is developed to simulate the experimental findings and make testable predictions of the behavior of the cardiac cells under different physiological conditions.

Simulation of the effects of moderate stimulation/inhibition of the β1-adrenergic signaling system and its components in mouse ventricular myocytes.

The β1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca(2+) concentration ([Ca(2+)]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of β1-adrenergic receptors (β1-ARs) on the action potential, Ca(2+) and Na(+) dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4).

A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes.

The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca(2+)]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure.

A mathematical model of the mouse ventricular myocyte contraction.

Mathematical models of cardiac function at the cellular level include three major components, such as electrical activity, Ca(2+) dynamics, and cellular shortening. We developed a model for mouse ventricular myocyte contraction which is based on our previously published comprehensive models of action potential and Ca(2+) handling mechanisms. The model was verified with extensive experimental data on mouse myocyte contraction at room temperature.

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

Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca(2+) 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 Ca(2+) handling of isolated TNF-α mice ventricular myocytes.

Heteropoda toxin 2 interaction with Kv4.3 and Kv4.1 reveals differences in gating modification.

Kv4 (Shal) potassium channels are responsible for the transient outward K(+) currents in mammalian hearts and central nervous systems. Heteropoda toxin 2 (HpTx2) is an inhibitor cysteine knot peptide toxin specific for Kv4 channels that inhibits gating of Kv4.3 in the voltage-dependent manner typical for this type of toxin.

A model of the interaction between N-type and C-type inactivation in Kv1.4 channels.

Kv1.4 channels are Shaker-related voltage-gated potassium channels with two distinct inactivation mechanisms. Fast N-type inactivation operates by a ball-and-chain mechanism.

Transmural heterogeneity of repolarization and Ca2+ handling in a model of mouse ventricular tissue.

Mouse hearts have a diversity of action potentials (APs) generated by the cardiac myocytes from different regions. Recent evidence shows that cells from the epicardial and endocardial regions of the mouse ventricle have a diversity in Ca(2+) handling properties as well as K(+) current expression. To examine the mechanisms of AP generation, propagation, and stability in transmurally heterogeneous tissue, we developed a comprehensive model of the mouse cardiac cells from the epicardial and endocardial regions of the heart.

Closed-state inactivation in Kv4.3 isoforms is differentially modulated by protein kinase C.

Kv4.3, with its complex open- and closed-state inactivation (CSI) characteristics, is a primary contributor to early cardiac repolarization. The two alternatively spliced forms, Kv4.

S3b amino acid substitutions and ancillary subunits alter the affinity of Heteropoda venatoria toxin 2 for Kv4.3.

Heteropoda venatoria toxin 2 (HpTx2) is an inhibitor cystine knot (ICK)-gating modifier toxin that selectively inhibits Kv4 channels. To characterize the molecular determinants of interaction, we performed alanine scanning of the Kv4.3 S3b region.

Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity.

The molecular heterogeneity of repolarizing currents produces significant spatial heterogeneity and/or dispersion of repolarization in many mammalian cardiac tissues. Transgenic mice are prominent experimental models for the study of the molecular basis of repolarization and arrhythmias. However, it is debated whether the small mouse heart can sustain physiologically relevant heterogeneity of repolarization.

W-7 modulates Kv4.3: pore block and Ca2+-calmodulin inhibition.

Ca(+)-calmodulin (Ca(2+)-CaM)-dependent protein kinase II (Ca(2+)/CaMKII) is an important regulator of cardiac ion channels, and its inhibition may be an approach for treatment of ventricular arrhythmias. Using the two-electrode voltage-clamp technique, we investigated the role of W-7, an inhibitor of Ca(2+)-occupied CaM, and KN-93, an inhibitor of Ca(2+)/CaMKII, on the K(v)4.3 channel in Xenopus laevis oocytes.

DPP10 is an inactivation modulatory protein of Kv4.3 and Kv1.4.

Voltage-gated K(+) channels exist in vivo as multiprotein complexes made up of pore-forming and ancillary subunits. To further our understanding of the role of a dipeptidyl peptidase-related ancillary subunit, DPP10, we expressed it with Kv4.3 and Kv1.

Time- and voltage-dependent components of Kv4.3 inactivation.

Kv4.3 inactivation is a complex multiexponential process, which can occur from both closed and open states. The fast component of inactivation is modulated by the N-terminus, but the mechanisms mediating the other components of inactivation are controversial.

Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family.

Kv4 voltage-gated K(+) channels are responsible for transient K(+) currents in the central nervous system and in the heart. HpTx2 is a peptide toxin that selectively inhibits these currents; making it a useful probe for understanding Kv4 channel structure and drug binding. Therefore, we developed a method to produce large amounts of recombinant HpTx2.

Bifurcation of synchronous oscillations into torus in a system of two reciprocally inhibitory silicon neurons: experimental observation and modeling.

Oscillatory activity in the central nervous system is associated with various functions, like motor control, memory formation, binding, and attention. Quasiperiodic oscillations are rarely discussed in the neurophysiological literature yet they may play a role in the nervous system both during normal function and disease. Here we use a physical system and a model to explore scenarios for how quasiperiodic oscillations might arise in neuronal networks.

Computer model of action potential of mouse ventricular myocytes.

We have developed a mathematical model of the mouse ventricular myocyte action potential (AP) from voltage-clamp data of the underlying currents and Ca2+ transients. Wherever possible, we used Markov models to represent the molecular structure and function of ion channels. The model includes detailed intracellular Ca2+ dynamics, with simulations of localized events such as sarcoplasmic Ca2+ release into a small intracellular volume bounded by the sarcolemma and sarcoplasmic reticulum.