Calcium Oscillations In Hepatocytes Research Articles

Hopf bifurcation control of calcium oscillations in hepatocytes

Hopf bifurcation control of calcium oscillations in hepatocytes

Establishing the stochastic nature of intracellular calcium oscillations from experimental data

Calcium has been established as a key messenger in both intra- and intercellular signaling. Experimentally observed intracellular calcium responses to different agonists show a variety of behaviors from simple spiking to complex oscillatory regimes. Here we study typical experimental traces of calcium oscillations in hepatocytes obtained in response to phenylephrine and ATP. The traces were analyzed with methods of nonlinear time series analysis in order to determine the stochastic/deterministic nature of the intracellular calcium oscillations. Despite the fact that the oscillations appear, visually, to be deterministic yet perturbed by noise, our analyses provide strong evidence that the measured calcium traces in hepatocytes are prevalently of stochastic nature. In particular, bursting calcium oscillations are temporally correlated Gaussian series distorted by a monotonic, instantaneous, time-independent function, whilst the spiking behavior appears to have a dynamical nonlinear component whereby the overall determinism level is still low. The biological importance of this finding is discussed in relation to the mechanisms incorporated in mathematical models as well as the role of stochasticity and determinism at cellular and tissue levels which resemble typical statistical and thermodynamic effects in physics.

Internal noise enhanced detection of hormonal signal through intracellular calcium oscillations

A variety of cell types respond to extracellular hormonal signals by repetitive intracellular calcium spikes. Here, by constructing a mesoscopic stochastic model for intracellular calcium oscillations in hepatocytes, we have investigated the influence of internal noise on the detection of sub-threshold hormonal signals using chemical Langevin equation (CLE) and Poisson approximation. It is found that stochastic calcium spikes appear when the internal noise is considered, and the regularity of the spike train undergoes a maximum with the variation of the internal noise level, indicating the occurrence of internal noise stochastic resonance (INSR). Since the magnitude of the internal noise is changed via the variation of the system size, the INSR also represents itself a kind of system size resonance.

Effects of gap junction to Ca 2+ and to IP 3 on the synchronization of intercellular calcium oscillations in hepatocytes

The frequency of free cytosolic calcium concentration ([Ca 2+]) oscillations elicited by a given agonist concentration differs between individual hepatocytes. However, in multicellular systems of rat hepatocytes and even in the intact liver, [Ca 2+] oscillations are synchronized and highly coordinated. In this paper, we have investigated theoretically the gap junction permeable to calcium and to IP 3 on intercellular synchronization by means of a mathematical model, respectively. It is shown that gap junction permeable to calcium and to IP 3 are effective on synchronizing calcium oscillations in coupled hepatocytes. Our theoretical results are similar either for the case of Ca 2+ acting as coordinating messenger or for the case of IP 3 as coordinating messenger. There exists an optimal coupling strength for a pair of connected hepatocytes. Appropriate coupling strength and IP 3 level can induce various harmonic locking of intercellular [Ca 2+] oscillations. Furthermore, a phase diagram in two-dimensional parameter space of the coupling strength and IP 3 level (or the velocity of IP 3 synthesis) has been predicted, in which the synchronization region is similar to Arnol'd tongue.

Model of Intercellular Calcium Oscillations in Hepatocytes: Synchronization of Heterogeneous Cells

Hepatocytes respond with repetitive cytosolic calcium spikes to stimulation by vasopressin and noradrenalin. In the intact liver, calcium oscillations occur in a synchronized fashion as periodic waves across whole liver lobules, but the mechanism of intercellular coupling remains unclear. Recently, it has been shown that individual hepatocytes can have very different intrinsic oscillation frequencies but become phase-locked when coupled by gap junctions. We investigate the gap junction hypothesis for intercellular synchronization by means of a mathematical model. It is shown that junctional calcium fluxes are effective in synchronizing calcium oscillations in coupled hepatocytes. An experimentally testable estimate is given for the junctional coupling coefficient required; it mainly depends on the degree of heterogeneity between cells. Intercellular synchronization by junctional calcium diffusion may occur also in other cell types exhibiting calcium-activated calcium release through InsP 3 receptors, if the gap junctional coupling is strong enough and the InsP 3 receptors are sufficiently sensitized by InsP 3.

Inositol-phosphoglycan inhibits calcium oscillations in hepatocytes by reducing calcium entry

Inositol-phosphoglycan (IPG) is a putative mediator of insulin action that has been shown to affect numerous biochemical processes. IPG, prepared from liver membranes, promptly inhibited phenylephrine- or vasopressin-induced [Ca 2+] i oscillations when perfused over Fura-2-dextran injected rat hepatocytes. An antibody to IPG suppressed the inhibitory effect of insulin on the [Ca 2+] i oscillations. Measurement of the rate of quench of cytoplasmic Fura-2 by extracellular Mn 2+ showed that Ca 2+ entry occurred continuously in the unstimulated cell and was not affected by phenylephrine or vasopressin. IPG, specifically, almost completely abolished the Mn 2+ quench rate. Elevated extracellular [Ca 2+] reversed the inhibitory effect of IPG on [Ca 2+] i oscillations. We conclude that IPG inhibits the hepatocyte Ca 2+ oscillator by reducing the continuous Ca 2+ influx that is required to sustain oscillations in [Ca 2+] i.