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J Sneyd

Publications and source records attributed to J Sneyd.

At least 19 recordsLinked to original sources
PubMed2006

A method for determining the dependence of calcium oscillations on inositol trisphosphate oscillations.

In some cell types, oscillations in the concentration of free intracellular calcium ([Ca2+]) are accompanied by oscillations in the concentration of inositol 1,4,5-trisphosphate ([IP3]). However, in most cell types it is still an open question as to whether oscillations in [IP3] are necessary for Ca2+ oscillations in vivo, or whether they merely follow passively. Using a wide range of models, we show that the response to an artificially applied pulse of IP3 can be used to distinguish between these two cases. Hence, we show that muscarinic receptor-mediated, long-period Ca2+ oscillations in pancreatic acinar cells depend on [IP3] oscillations, whereas short-period Ca2+ oscillations in airway smooth muscle do not.

Animals↗
PubMed2005

Mathematical modelling of prolactin-receptor interaction and the corollary for prolactin receptor gene expression in skin.

A mathematical model of prolactin regulating its own receptors was developed, and compared with experimental data on a qualitative level. The model incorporates the kinetics of prolactin-receptor interactions and subsequent signalling by prolactin-receptor dimers to regulate the production of receptor mRNA and hence the receptor population. The model relates changes in plasma prolactin concentration to prolactin receptor (PRLR) gene expression, and can be used for predictive purposes. The cell signalling that leads to the activation of target genes, and the mechanisms for regulation of transcription, were treated empirically in the model. The model's parameters were adjusted so that model simulations agreed with experimentally observed responses to administration of prolactin in sheep. In particular, the model correctly predicts insensitivity of receptor mRNA regulation to a series of subcutaneous injections of prolactin, versus sensitivity to prolonged infusion of prolactin. In the latter case, response was an acute down-regulation followed by a prolonged up-regulation of mRNA, with the magnitude of the up-regulation increasing with the duration of infusion period. The model demonstrates the feasibility of predicting the in vivo response of prolactin target genes to external manipulation of plasma prolactin, and could provide a useful tool for identifying optimal prolactin treatments for desirable outcomes.

Animals↗
PubMed2004

Models of the inositol trisphosphate receptor.

The inositol (1,4,5)-trisphosphate receptor (IPR) plays a crucial role in calcium dynamics in a wide range of cell types, and is often a central feature in quantitative models of calcium oscillations and waves. We review deterministic and stochastic mathematical models of the IPR, from the earliest ones of the 1970s and 1980s, to the most recent. The effects of IPR stochasticity on Ca2+ dynamics are briefly discussed.

Allosteric Site↗
PubMed2004

Calcium oscillations in a triplet of pancreatic acinar cells.

We use a mathematical model of calcium dynamics in pancreatic acinar cells to investigate calcium oscillations in a ring of three coupled cells. A connected group of cells is modeled in two different ways: 1), as coupled point oscillators, each oscillator being described by a spatially homogeneous model; and 2), as spatially distributed cells coupled along their common boundaries by gap-junctional diffusion of inositol trisphosphate and/or calcium. We show that, although the point-oscillator model gives a reasonably accurate general picture, the behavior of the spatially distributed cells cannot always be predicted from the simpler analysis; spatially distributed diffusion and cell geometry both play important roles in determining behavior. In particular, oscillations in which two cells are in synchrony, with the third phase-locked but not synchronous, appears to be more dominant in the spatially distributed model than in the point-oscillator model. In both types of model, intercellular coupling leads to a variety of synchronous, phase-locked, or asynchronous behaviors. For some parameter values there are multiple, simultaneous stable types of oscillation. We predict 1), that intercellular calcium diffusion is necessary and sufficient to coordinate the responses in neighboring cells; 2), that the function of intercellular inositol trisphosphate diffusion is to smooth out any concentration differences between the cells, thus making it easier for the diffusion of calcium to synchronize the oscillations; 3), that groups of coupled cells will tend to respond in a clumped manner, with groups of synchronized cells, rather than with regular phase-locked periodic intercellular waves; and 4), that enzyme secretion is maximized by the presence of a pacemaker cell in each cluster which drives the other cells at a frequency greater than their intrinsic frequency.

Animals↗
PubMed2004

Control of calcium oscillations by membrane fluxes.

It is known that Ca(2+) influx plays an important role in the modulation of inositol trisphosphate-generated Ca(2+) oscillations, but controversy over the mechanisms underlying these effects exists. In addition, the effects of blocking membrane transport or reducing Ca(2+) entry vary from one cell type to another; in some cell types oscillations persist in the absence of Ca(2+) entry (although their frequency is affected), whereas in other cell types oscillations depend on Ca(2+) entry. We present theoretical and experimental evidence that membrane transport can control oscillations by controlling the total amount of Ca(2+) in the cell (the Ca(2+) load). Our model predicts that the cell can be balanced at a point where small changes in the Ca(2+) load can move the cell into or out of oscillatory regions, resulting in the appearance or disappearance of oscillations. Our theoretical predictions are verified by experimental results from HEK293 cells. We predict that the role of Ca(2+) influx during an oscillation is to replenish the Ca(2+) load of the cell. Despite this prediction, even during the peak of an oscillation the cell or the endoplasmic reticulum may not be measurably depleted of Ca(2+).

Calcium↗
PubMed2003

A model of calcium waves in pancreatic and parotid acinar cells.

We construct a mathematical model of Ca(2+) wave propagation in pancreatic and parotid acinar cells. Ca(2+) release is via inositol trisphosphate receptors and ryanodine receptors that are distributed heterogeneously through the cell. The apical and basal regions are separated by a region containing the mitochondria. In response to a whole-cell, homogeneous application of inositol trisphosphate (IP(3)), the model predicts that 1), at lower concentrations of IP(3), the intracellular waves in pancreatic cells begin in the apical region and are actively propagated across the basal region by Ca(2+) release through ryanodine receptors; 2), at higher [IP(3)], the waves in pancreatic and parotid cells are not true waves but rather apparent waves, formed as the result of sequential activation of inositol trisphosphate receptors in the apical and basal regions; 3), the differences in wave propagation in pancreatic and parotid cells can be explained in part by differences in inositol trisphosphate receptor density; 4), in pancreatic cells, increased Ca(2+) uptake by the mitochondria is capable of restricting Ca(2+) responses to the apical region, but that this happens only for a relatively narrow range of [IP(3)]; and 5), at higher [IP(3)], the apical and basal regions of the cell act as coupled Ca(2+) oscillators, with the basal region partially entrained to the apical region.

Animals↗
PubMed2000

Targeted phosphorylation of inositol 1,4,5-trisphosphate receptors selectively inhibits localized Ca2+ release and shapes oscillatory Ca2+ signals.

The current study provides biochemical and functional evidence that the targeting of protein kinase A (PKA) to sites of localized Ca(2+) release confers rapid, specific phosphoregulation of Ca(2+) signaling in pancreatic acinar cells. Regulatory control of Ca(2+) release by PKA-dependent phosphorylation of inositol 1,4, 5-trisphosphate (InsP(3)) receptors was investigated by monitoring Ca(2+) dynamics in pancreatic acinar cells evoked by the flash photolysis of caged InsP(3) prior to and following PKA activation. Ca(2+) dynamics were imaged with high temporal resolution by digital imaging and electrophysiological methods. The whole cell patch clamp technique was used to introduce caged compounds and to record the activity of a Ca(2+)-activated Cl(-) current. Photolysis of low concentrations of caged InsP(3) evoked Cl(-) currents that were inhibited by treatment with dibutryl-cAMP or forskolin. In contrast, PKA activators had no significant inhibitory effect on the activation of Cl(-) current evoked by uncaging Ca(2+) or by the photolytic release of higher concentrations of InsP(3). Treatment with Rp-adenosine-3',5'-cyclic monophoshorothioate, a selective inhibitor of PKA, or with Ht31, a peptide known to disrupt the targeting of PKA, largely abolished forskolin-induced inhibition of Ca(2+) release. Further evidence for the targeting of PKA to the sites of Ca(2+) mobilization was revealed using immunocytochemical methods demonstrating that the R(IIbeta) subunit of PKA was localized to the apical regions of acinar cells and co-immunoprecipitated with the type III but not the type I or type II InsP(3) receptors. Finally, we demonstrate that the pattern of signaling evoked by acetylcholine can be converted to one that is more "CCK-like" by raising cAMP levels. Our data provide a simple mechanism by which distinct oscillatory Ca(2+) patterns can be shaped.

Animals↗
PubMed1999

Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor: A possible mechanism for agonist-specific calcium oscillations in pancreatic acinar cells.

The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10-12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (>100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675-2681), and reproduce both short-period, raised baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81-84). We use the model to predict the effect of the removal of external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.

Acetylcholine↗
PubMed1998

Analysis of a reduced model of corticotroph action potentials.

We have previously described a model for corticotroph plasma membrane electrophysiology [LeBeau et al. (1997). Biophysical Journal 73, 1263-1275]. The model is a Hodgkin-Huxley-like formalism consisting of six coupled ordinary differential equations. Analysis of this model showed that Ca2+ action potentials could be induced by an increase in the L-type voltage-sensitive Ca2+ current. Thus we have demonstrated a putative causal link between an increase in the corticotroph Ca2+ current and action potential generation. We report here the reduction of the model to one with three equations, the behaviour of which was found to correspond well with that of the full model. The reduced model was then subjected to fast-slow subsystem analysis, which revealed the mechanistic interaction between the membrane potential and intracellular Ca2+ concentration that underlies action potential generation. Insights obtained from this analysis were used to investigate experimentally observed aspects of corticotroph electrophysiology such as spontaneous electrical activity, bursting action potentials, and observations from anode break excitation experiments.

Action Potentials↗
PubMed1998

Calcium waves and oscillations driven by an intercellular gradient of inositol (1,4,5)-trisphosphate.

In response to a local mechanical stimulus, mixed glial cells initially exhibit a propagating intercellular Ca2+ wave. Subsequently, cells within a zone, at a specific distance from the stimulated cell, display asynchronous intracellular Ca2+ oscillations. The experimental hypothesis that the initial Ca2+ wave could be mediated by the passive diffusion of inositol (1,4,5)-trisphosphate (IP3) from the stimulated cell has been verified by model simulations. Further simulations with the same model also show that Ca2+ oscillations can only occur within model cells when the IP3 concentration is within a specific range. Thus, this passive diffusion model predicts (a) that the IP3 concentration gradient established in the cells following mechanical stimulation will initiate Ca2+ oscillations in cells in a specific zone along this gradient and (b) that different Ca2+ oscillatory patterns will occur within a specified oscillatory zone. Both of these predictions have been confirmed by experimental data. The failure of experimentally observed Ca2+ oscillations to approach synchrony or entrain indicates a low intercellular calcium permeability of about 0.1 micron/s, and further suggests that Ca2+ does not appear to act as a significant messenger in the initiation of these intercellular Ca2+ waves or oscillations. In conclusion a passive diffusion of IP3, but not Ca2+, through gap junctions remains the preferred hypothesis for the mechanism underlying mechanically-stimulated intercellular calcium waves and Ca2+ oscillations.

Binding Sites↗
PubMed1998

Intercellular spiral waves of calcium.

Intercellular calcium waves have been observed in a large number of cell types, and are known to result from a variety of stimuli, including mechanical or hormonal stimulation. Recently, spiral intercellular waves of calcium have been observed in slices of hippocampal tissue. We use an existing model to study the properties of spiral intercellular calcium waves. Although intercellular spiral waves are well known in the context of cardiac muscle, due to the small value of the calcium diffusion coefficient intercellular calcium waves have fundamentally different properties. We show that homogenisation techniques give a good estimate for the plane wave speed, but do not describe spiral behaviour well. Using an expression for the effective diffusion coefficient we estimate the intercellular calcium permeability in liver. For the bistable equation, we derive an analytic estimate for the value of the intercellular permeability at which wave propagation fails. In the calcium wave model, we show numerically that the spiral period is first a decreasing, then an increasing, function of the intercellular permeability. We hypothesise that this is because the curvature of the spiral core is unimportant at low permeability, the period being approximately set instead by the speed of a plane wave along a line of coupled cells in one dimension.

Animals↗
PubMed1998

A simple method for high temporal resolution calcium imaging with dual excitation dyes.

Calcium-sensitive dual excitation dyes, such as fura-2, are now widely used to measure the free calcium concentration ([Ca2+]) in living cells. Preferentially, [Ca2+] is calculated in a ratiometric manner, but if calcium images need to be acquired at high temporal resolution, a potential drawback of ratiometry is that it requires equally fast switching of the excitation light between two wavelengths. To circumvent continuous excitation switching, some investigators have devised methods for calculating [Ca2+] from single-wavelength measurements combined with the acquisition of a single ratiometric pair of fluorescence images at the start of the recording. These methods, however, are based on the assumption that the concentration of the dye does not change during the experiment, a condition that is often not fulfilled. We describe here a method of single-wavelength calcium imaging, in which the dye concentration is estimated from ratiometric fluorescence image pairs acquired at regular intervals during the recording period, that furthermore includes a correction for the changing dye concentration in the calculation of [Ca2+].

Animals↗
PubMed1997

Generation of action potentials in a mathematical model of corticotrophs.

Corticotropin-releasing hormone (CRH) is an important regulator of adrenocorticotropin (ACTH) secretion from pituitary corticotroph cells. The intracellular signaling system that underlies this process involves modulation of voltage-sensitive Ca2+ channel activity, which leads to the generation of Ca2+ action potentials and influx of Ca2+. However, the mechanisms by which Ca2+ channel activity is modulated in corticotrophs are not currently known. We investigated this process in a Hodgkin-Huxley-type mathematical model of corticotroph plasma membrane electrical responses. We found that an increase in the L-type Ca2+ current was sufficient to generate action potentials from a previously resting state of the model. The increase in the L-type current could be elicited by either a shift in the voltage dependence of the current toward more negative potentials, or by an increase in the conductance of the current. Although either of these mechanisms is potentially responsible for the generation of action potentials, previous experimental evidence favors the former mechanism, with the magnitude of the shift required being consistent with the experimental findings. The model also shows that the T-type Ca2+ current plays a role in setting the excitability of the plasma membrane, but does not appear to contribute in a dynamic manner to action potential generation. Inhibition of a K+ conductance that is active at rest also affects the excitability of the plasma membrane.

Action Potentials↗
PubMed1995

Mechanisms of calcium oscillations and waves: a quantitative analysis.

Oscillations and waves of increased intracellular free calcium concentration ([Ca2+]i) are observed in a wide range of cell types. Because of their inherent nonlinear nature and the consequent unreliability of intuitive approaches, mathematical modeling has an important role to play in the study of these phenomena. One important class of oscillations and waves is dependent on the presence of inositol (1,4,5)-trisphosphate (IP3), which releases Ca2+ from internal stores via the IP3 receptor/Ca2+ channel. With the minimum possible mathematical formalism, we review mechanistic models for IP3-dependent Ca2+ oscillations and waves. These models are based on the regulation of the IP3 receptor by both IP3 and Ca2+, and incorporate experimental data on the steady-state and kinetic properties of the receptor. The extension of the models to describe intracellular and intercellular Ca2+ waves is considered.

Animals↗
PubMed1995

Intercellular calcium waves mediated by diffusion of inositol trisphosphate: a two-dimensional model.

In response to mechanical stimulation of a single cell, airway epithelial cells in culture exhibit a wave of increased intracellular free Ca2+ concentration that spreads from cell to cell over a limited distance through the culture. We present a detailed analysis of the intercellular wave in a two-dimensional sheet of cells. The model is based on the hypothesis that the wave is the result of diffusion of inositol trisphosphate (IP3) from the stimulated cell. The two-dimensional model agrees well with experimental data and makes the following quantitative predictions: as the distance from the stimulated cells increases, 1) the intercellular delay increases exponentially, 2) the intracellular wave speed decreases exponentially, and 3) the arrival time increases exponentially. Furthermore, 4) a proportion of the cells at the periphery of the response will exhibit waves of decreased amplitude, 5) the intercellular membrane permeability to IP3 must be approximately 2 microns/s or greater, and 6) the ratio of the maximum concentration of IP3 in the stimulated cell to the Km of the IP3 receptor (with respect to IP3) must be approximately 300 or greater. These predictions constitute a rigorous test of the hypothesis that the intercellular Ca2+ waves are mediated by IP3 diffusion.

Animals↗
PubMed1994

A profile analysis of propagating calcium waves.

The identity of the wave messenger mediating the propagation of intracellular Ca2+ waves in a variety of cells is currently controversial. There is disagreement as to whether the observed waves are mediated by the diffusion of Ca2+ or by the diffusion of inositol 1,4,5-trisphosphate. Resolution of this question will help to elucidate the mechanisms underlying intracellular Ca2+ waves and oscillations. It has been suggested that the diffusion coefficient of the wave messenger, D, may be evaluated by means of the profile equation, D = c lambda, where c is the wave speed, and lambda is the space constant of the wave front. We show that this equation is not, in general, correct. We derive a more comprehensive form of the profile equation, including the effect of buffering of the wave messenger, and show that the profile equation may be used to estimate the diffusion coefficient of the wave messenger only if the details of the reaction and buffering kinetics are known.

Buffers↗