Hysteresis and bi-stability by an interplay of calcium oscillations and action potential firing

Many cell types exhibit oscillatory activity, such as repetitive action potential firing due to the Hodgkin-Huxley dynamics of ion channels in the cell membrane or reveal intracellular inositol triphosphate (IP$_3$) mediated calcium oscillations (CaOs) by calcium-induced calcium release channels (IP$_3$-receptor) in the membrane of the endoplasmic reticulum (ER). The dynamics of the excitable membrane and that of the IP$_3$-mediated CaOs have been the subject of many studies. However, the interaction between the excitable cell membrane and IP$_3$-mediated CaOs, which are coupled by cytosolic calcium which affects the dynamics of both, has not been studied. This study for the first time applied stability analysis to investigate the dynamic behavior of a model, which includes both an excitable membrane and an intracellular IP$_3$-mediated calcium oscillator. Taking the IP$_3$ concentration as a control parameter, the model exhibits a novel rich spectrum of stable and unstable states with hysteresis. The four stable states of the model correspond in detail to previously reported growth-state dependent states of the membrane potential of normal rat kidney fibroblasts in cell culture. The hysteresis is most pronounced for experimentally observed parameter values of the model, suggesting a functional importance of hysteresis. This study shows that the four growth-dependent cell states may not reflect the behavior of cells that have differentiated into different cell types with different properties, but simply reflect four different states of a single cell type, that is characterized by a single model.Comment: 29 pages, 6 figure

Novel Approaches to Treat Experimental Pulmonary Arterial Hypertension: A Review

Background. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by an increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current treatments can improve symptoms and reduce severity of the hemodynamic disorder but gradual deterioration in their condition often necessitates a lung transplant. Methods and Results. In experimental models of PAH, particularly the model of monocrotaline-induced pulmonary hypertension, efficacious treatment options tested so far include a spectrum of pharmacologic agents with actions such as anti-mitogenic, proendothelial function, proangiogenic, antiinflammatory and antioxidative. Emerging trends in PAH treatment are gene and cell therapy and their combination, like (progenitor) cells enriched with eNOS or VEGF gene. More animal data should be collected to investigate optimal cell type, in vitro cell transduction, route of administration, and number of cells to inject. Several recently discovered and experimentally tested interventions bear potential for therapeutic purposes in humans or have been shown already to be effective in PAH patients leading to improved life expectation and better quality of life. Conclusion. Since many patients remain symptomatic despite therapy, we should encourage research in animal models of PAH and implement promising treatments in homogeneous groups of PAH patients

Analysis of decaying unitary currents in on-cell patches of cells with a high membrane resistance

Under nonideal voltage-clamp conditions, unitary currents in the cell- attached patch (CAP) configuration of the patch-clamp technique are decaying instead of rectangular. From these data, four parameters can be determined when multiple identical channels are present. We analyzed an electrical equivalent circuit of the CAP configuration. This analysis yielded, for single-channel resistance, attached-cell membrane resistance, patch resistance, and attached-cell membrane capacitance, a set of different equations to calculate their values from these four parameters. To choose the most robust equation, those that yielded the same resistor/capacitance were compared on the basis of their sensitivity for inevitable deviations of the parameters from their nominal values. The results of our theoretical study are of methodological interest: 1) because they confirm that, under special conditions, CAP measurements can be used to measure electrical membrane properties of intact cells (this is important inasmuch as the CAP is the only configuration in which the cytoplasm of cells remains undisturbed) and 2) because we identify the level of voltage clamp and the equations with which the electrical properties can be determined with optimal accuracy

Microfoci of oxidative stress increase pro-arrhythmic risk as revealed by patterned illumination of optogenetically engineered myocardial cultures

Cardiolog

Voltage-activated ionic channels and conductances in embryonic chick osteoblast cultures

Patch-clamp measurements were made on osteoblast-like cells isolated from embryonic chick calvaria. Cell-attachedpatch measurements revealed two types of high conductance (100-250 pS) channels, which rapidly activated upon 50-100 mV depolarization. One type showed sustained and the other transient activation over a 10-sec period of depolarization. The single-channel conductances of these channel types were about 100 or 250 pS, depending on whether the pipettes were filled with a low K+ (3 mm) or high K+ (143 mm) saline, respectively. The different reversal potentials under these conditions were consistent with at least K+ conduction. Whole-cell measurements revealed the existence of two types of outward rectifying conductances. The first type conducts K+ ions and activates within 20-200 msec (depending on the stimulus) upon depolarizing voltage steps from -30 mV. It inactivates almost completely with a time constant of 2-3 sec. Recovery from inactivation is biphasic with an initial rapid phase (1-2 sec) followed by a slow phase (>20 sec). The second whole-cell conductance activates at positive membrane potentials of >+50 mV. It also rapidly turns on upon depolarizing voltage steps. Activation may partly disappear at the higher voltages. Its single channels of 140 pS conductance were identified in the whole cell and did conduct K+ ions but were not highly Cl- or Na+ selective. The results show that osteoblasts may express various types of voltage controlled ionic channels. We predict a role for such channels in mineral metabolism of bone tissue and its control by osteoblasts