Stochastic noise and synchronisation during Dictyostelium aggregation make cAMP oscillations robust

The molecular network, which underlies the oscillations in the concentration of adenosine 3′, 5′-cyclic monophosphate (cAMP) during the aggregation phase of starvation-induced development in Dictyostelium discoideum, achieves remarkable levels of robust performance in the face of environmental variations and cellular heterogeneity. However, the reasons for this robustness remain poorly understood. Tools and concepts from the field of control engineering provide powerful methods for uncovering the mechanisms underlying the robustness of these types of biological systems. Using such methods, two important factors contributing to the robustness of cAMP oscillations in Dictyostelium are revealed. First, stochastic fluctuations in the molecular interactions of the intracellular network, arising from random or directional noise and biological sources, play an important role in preserving stable oscillations in the face of variations in the kinetics of the network. Second, synchronisation of the aggregating cells through the diffusion of extracellular cAMP appears to be a key factor in ensuring robustness to cell-to-cell variations of the oscillatory waves of cAMP observed in Dictyostelium cell cultures. The conclusions have important general implications for the robustness of oscillating biomolecular networks (whether seen at organism, cell, or intracellular levels and including circadian clocks or Ca2+ oscillations, etc.), and suggest that such analysis can be conducted more reliably by using models including stochastic simulations, even in the case where molecular concentrations are very high

Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach

BACKGROUND: Calmodulin is an important multifunctional molecule that regulates the activities of a large number of proteins in the cell. Calcium binding induces conformational transitions in calmodulin that make it specifically active to particular target proteins. The precise mechanisms underlying calcium binding to calmodulin are still, however, quite poorly understood. RESULTS: In this study, we adopt a structural systems biology approach and develop a mathematical model to investigate various types of cooperative calcium-calmodulin interactions. We compare the predictions of our analysis with physiological dose-response curves taken from the literature, in order to provide a quantitative comparison of the effects of different mechanisms of cooperativity on calcium-calmodulin interactions. The results of our analysis reduce the gap between current understanding of intracellular calmodulin function at the structural level and physiological calcium-dependent calmodulin target activation experiments. CONCLUSION: Our model predicts that the specificity and selectivity of CaM target regulation is likely to be due to the following factors: variations in the target-specific Ca2+ dissociation and cooperatively effected dissociation constants, and variations in the number of Ca2+ ions required to bind CaM for target activation

Crosstalk between G-protein and Ca2+ pathways switches intracellular cAMP levels

Cyclic adenosine monophosphate and cyclic guanosine monophosphate are universal intracellular messengers whose concentrations are regulated by molecular networks comprised of different isoforms of the synthases adenylate cyclase or guanylate cyclase and the phosphodiesterases which degrade these compounds. In this paper, we employ a systems biology approach to develop mathematical models of these networks that, for the first time, take into account the different biochemical properties of the isoforms involved. To investigate the mechanisms underlying the joint regulation of cAMP and cGMP, we apply our models to analyse the regulation of cilia beat frequency in Paramecium by Ca(2+). Based on our analysis of these models, we propose that the diversity of isoform combinations that occurs in living cells provides an explanation for the huge variety of intracellular processes that are dependent on these networks. The inclusion of both G-protein receptor and Ca(2+)-dependent regulation of AC in our models allows us to propose a new explanation for the switching properties of G-protein subunits involved in nucleotide regulation. Analysis of the models suggests that, depending on whether the G-protein subunit is bound to AC, Ca(2+) can either activate or inhibit AC in a concentration-dependent manner. The resulting analysis provides an explanation for previous experimental results that showed that alterations in Ca(2+) concentrations can either increase or decrease cilia beat frequency over particular Ca(2+) concentration ranges

Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

Under conditions of starvation, Dictyostelium cells begin a programme of development during which they aggregate to form a multicellular structure by chemotaxis, guided by propagating waves of cyclic AMP that are relayed robustly from cell to cell. In this paper, we develop and analyse a new model for the intracellular and extracellular cAMP dependent processes that regulate Dictyostelium migration. The model allows, for the first time, a quantitative analysis of the dynamic interactions between calcium, IP(3) and G protein-dependent modules that are shown to be key to the generation of robust cAMP oscillations in Dictyostelium cells. The model provides a mechanistic explanation for the transient increase in cytosolic free Ca(2+) concentration seen in recent experiments with the application of the calmodulin inhibitor calmidazolium (R24571) to Dictyostelium cells, and also allows elucidation of the effects of varying both the conductivity of stretch-activated channels and the concentration of external phosphodiesterase on the oscillatory regime of an individual cell. A rigorous analysis of the robustness of the new model shows that interactions between the different modules significantly reduce the sensitivity of the resulting cAMP oscillations to variations in the kinetics of different Dictyostelium cells, an essential requirement for the generation of the spatially and temporally synchronised chemoattractant cAMP waves that guide Dictyostelium aggregation

Wide-band information transmission at the calyx of Held

We use a mathematical model of the calyx of Held to explore information transmission at this giant glutamatergic synapse. The significant depression of the postsynaptic response to repeated stimulation in vitro is a result of various activity-dependent processes in multiple time scales, which can be reproduced by multiexponential functions in this model. When stimulated by Poisson-distributed spike trains the amplitude of the postsynaptic current varies considerably with the preceding interspike intervals. Here we quantify the information contained in the postsynaptic current amplitude about preceding interspike intervals and determine the impact of different pre- and postsynaptic factors on information transmission. The mutual information between presynaptic spike times and the amplitude of the postsynaptic response in general decreases as the mean stimulation rate increases, but remains high even at frequencies greater than 100 Hz, unlike at many neocortical synapses. The maintenance of information transmission is attributable largely to vesicle recycling rates at low frequencies of stimulation, shifting to vesicle release probability at high frequencies. Also at higher frequencies the synapse operates largely in a release ready mode in which most release sites contain a release-ready vesicle and release probabilities are low

Trideset pet godina muzejskih kataloga Galerije Klovićevih dvora

Kvalitetan katalog dopunjava izložbu i čini je cjelovitom te ostaje kao trajno svjedočanstvo o njoj. Dok izložbe imaju svoj vijek trajanja, katalozi za buduće korisnike čuvaju informacije, dosege i rezultate do kojih se došlo tijekom pripreme izložbe. Izložbe priređene u 35-godišnjem djelovanju Galerije Klovićevi dvori ostavile su dubok trag u našoj kulturi, što potvrđuje još uvijek živo zanimanje korisnika za kataloge tih izložaba, od kojih su neka izdanja i rasprodana

A biophysical model of short-term plasticity at the calyx of Held

The calyx of Held is a giant glutamatergic synapse in the auditory system and displays multiple forms of short-term facilitation and depression. This study presents a detailed model of short-term plasticity at this synapse. The main components of the model are the presynaptic vesicle dynamics, which include passive and activity-dependent recycling, calcium-dependent exocytosis and the postsynaptic AMPA receptor kinetics. The behaviour of the model is compared to experimental data and reproduces the time course and amplitude of synaptic depression during repetitive stimulation at different frequencies. A comparison of different manipulations of the model shows that accurate fits require the inclusion of fast activity-dependent vesicle recycling and a limited number of vesicle docking sites at each active zone