Yukiko Himeno

Ionic mechanisms and Ca2+ dynamics underlying the glucose response of pancreatic β cells: a simulation study.

To clarify the mechanisms underlying the pancreatic β-cell response to varying glucose concentrations ([G]), electrophysiological findings were integrated into a mathematical cell model. The Ca2+ dynamics of the endoplasmic reticulum (ER) were also improved. The model was validated by demonstrating quiescent potential, burst–interburst electrical events accompanied by Ca2+ transients, and continuous firing of action potentials over [G] ranges of 0–6, 7–18, and >19 mM, respectively. These responses to glucose were completely reversible. The action potential, input impedance, and Ca2+ transients were in good agreement with experimental measurements. The ionic mechanisms underlying the burst–interburst rhythm were investigated by lead potential analysis, which quantified the contributions of individual current components. This analysis demonstrated that slow potential changes during the interburst period were attributable to modifications of ion channels or transporters by intracellular ions and/or metabolites to different degrees depending on [G]. The predominant role of adenosine triphosphate–sensitive K+ current in switching on and off the repetitive firing of action potentials at 8 mM [G] was taken over at a higher [G] by Ca2+- or Na+-dependent currents, which were generated by the plasma membrane Ca2+ pump, Na+/K+ pump, Na+/Ca2+ exchanger, and TRPM channel. Accumulation and release of Ca2+ by the ER also had a strong influence on the slow electrical rhythm. We conclude that the present mathematical model is useful for quantifying the role of individual functional components in the whole cell responses based on experimental findings.

Ionic Mechanisms Underlying the Positive Chronotropy Induced by β1-Adrenergic Stimulation in Guinea Pig Sinoatrial Node Cells: a Simulation Study

Positive chronotropy induced by beta1-adrenergic stimulation is achieved by multiple interactions of ion channels and transporters in sinoatrial node pacemaker cells (SANs). To investigate the ionic mechanisms, we updated our SAN model developed in 2003 and incorporated the beta1-adrenergic signaling cascade developed by Kuzumoto et al. (2007). Since the slow component of the delayed rectifier K+ current (IKs) is one of the major targets of the beta1-adrenergic cascade, we developed a guinea pig model with a large IKs. The new model provided a good representation of the experimental characteristics of SANs. A comparison of individual current during diastole recorded before and after beta1-adrenergic stimulation clearly showed the negative shift of the L-type Ca2+ current (ICaL) takeoff potential, enlargement of the sustained inward current (I st), and the hyperpolarization-activated nonselective cation current (Iha) played major roles in increasing the firing frequency. Deactivation of IKs during diastole scarcely contributed to the time-dependent decrease in membrane K+ conductance, which was the major mechanism for slow diastolic depolarization, as indicated by calculating the instantaneous equilibrium potential (lead potential). This was because the activation of IKs during the preceding action potential was negligibly small. However, IKs was important in counterbalancing the increase in ICaL and the Na+/Ca2+ exchange current (INaCa), which otherwise compromised the positive chronotropic effect by elongating the action potential duration. Enhanced Ca2+ release from the sarcoplasmic reticulum failed to induce an obvious chronotropic effect in our model.

A Novel Method to Quantify Contribution of Channels and Transporters to Membrane Potential Dynamics

The action potential, once triggered in ventricular or atrial myocytes, automatically proceeds on its time course or is generated spontaneously in sinoatrial node pacemaker cells. It is induced by complex interactions among such cellular components as ion channels, transporters, intracellular ion concentrations, and signaling molecules. We have developed what is, to our knowledge, a new method using a mathematical model to quantify the contribution of each cellular component to the automatic time courses of the action potential. In this method, an equilibrium value, which the membrane potential is approaching at a given moment, is calculated along the time course of the membrane potential. The calculation itself is based on the time-varying conductance and the reversal potentials of individual ion channels and electrogenic ion transporters. Since the equilibrium potential moves in advance of the membrane potential change, we refer to it as the lead potential, V(L). The contribution of an individual current was successfully quantified by comparing dV(L)/dt before and after fixing the time-dependent change of a component of interest, such as the variations in the open probability of a channel or the turnover rate of an ion transporter. In addition to the action potential, the lead-potential analysis should also be applicable in all types of membrane excitation in many different kinds of cells.

Mechanisms underlying the volume regulation of interstitial fluid by capillaries: a simulation study

Background Control of the extracellular fluid volume is one of the most indispensable issues for homeostasis of the internal milieu. However, complex interdependence of the pressures involved in determination of fluid exchange makes it difficult to predict a steady-state tissue volume under various physiological conditions without mathematical approaches. Methods Here, we developed a capillary model based on the Starlings principle, which allowed us to clarify the mechanisms of the interstitial-fluid volume regulation. Three well known safety factors against edema: (1) low tissue compliance in negative pressure ranges; (2) lymphatic flow driven by the tissue pressure; and (3) protein washout by the lymph, were incorporated into the model in sequence. Results An increase in blood pressure at the venous end of the capillary induced an interstitial-fluid volume increase, which, in turn, reduced negative tissue pressure to prevent edema. The lymphatic flow alleviated the edema by both carrying fluid away from the tissue and decreasing the colloidal osmotic pressure. From the model incorporating all three factors, we found that the interstitial-fluid volume changed quickly after the blood pressure change, and that the protein movement towards a certain equilibrium point followed the volume change. Conclusion Mathematical analyses revealed that the system of the capillary is stable near the equilibrium point at steady state and normal physiological capillary pressure. The time course of the tissue-volume change was determined by two kinetic mechanisms: rapid fluid exchange and slow protein fluxes.

Ionic Basis of the Pacemaker Activity of SA Node Revealed by the Lead Potential Analysis

Ionic mechanisms of spontaneous action potential in sinoatrial (SA) node pacemaker cells have been discussed for decades. Although a number of theoretical studies have proposed different mathematical models, no scientific consensus has been achieved yet, because of the complexity and variations in experimental findings used for developing models. Here, we introduce a theoretical method in simulation study, the lead potential analysis, which enabled us to isolate the contribution of individual currents from the secondary effect of modified channel activities. We compared three models, suggesting different ionic mechanisms (Himeno et al. model, Kurata et al. model, and Maltsev and Lakatta model), and contributions of Ca2+ through activation of I NaCa is estimated. Finally, the effect of catecholamine stimulation is discussed based on a SA node cell model with β1-adrenergic signaling cascade and mechanisms of the positive chronotropy are analyzed.

A simulation study on the constancy of cardiac energy metabolites during workload transition.

The cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant during physiological cardiac workload transition. How this is accomplished is not yet clarified, though Ca2+ has been suggested to be one of the possible mechanisms. We constructed a detailed mathematical model of cardiac mitochondria based on experimental data and studied whether known Ca2+‐dependent regulation mechanisms play roles in the metabolite constancy. Model simulations revealed that the Ca2+‐dependent regulation mechanisms have important roles under the in vitro condition of isolated mitochondria where malate and glutamate were mitochondrial substrates, while they have only a minor role and the composition of substrates has marked influence on the metabolite constancy during workload transition under the simulated in vivo condition where many substrates exist. These results help us understand the regulation mechanisms of cardiac energy metabolism during physiological cardiac workload transition.