On the phase space structure of IP3induced Ca2+signalling and concepts for predictive modeling (original) (raw)
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The role of IP3R clustering in Ca2+ signalinG
Genome informatics. International Conference on Genome Informatics, 2008
Ca(2+) is the most important second messenger controlling a variety of intracellular processes by oscillations of the cytosolic Ca(2+) concentration. These oscillations occur by Ca(2+) release from the endoplasmic reticulum (ER) into the cytosol through channels and the re-uptake of Ca(2+) into the ER by pumps. A common channel type present in many cell types is the inositol trisphosphate receptor (IP(3)R), which is activated by IP(3) and Ca(2+) itself leading to Ca(2+) induced Ca(2+) release (CICR). We have shown in an experimental study, that Ca(2+) oscillations are sequences of random spikes that occur by wave nucleation. We use here our recently developed model for Ca(2+) dynamics in 3 dimension to illuminate the role of IP(3)R clustering within spatial extended systems.
Timescales of IP3-Evoked Ca2+ Spikes Emerge from Ca2+ Puffs Only at the Cellular Level
Biophysical Journal, 2011
The behavior of biological systems is determined by the properties of their component molecules, but the interactions are usually too complex to understand fully how molecular behavior generates cellular behavior. Ca(2+) signaling by inositol trisphosphate receptors (IP(3)R) offers an opportunity to understand this relationship because the cellular behavior is defined largely by Ca(2+)-mediated interactions between IP(3)R. Ca(2+) released by a cluster of IP(3)R (giving a local Ca(2+) puff) diffuses and ignites the behavior of neighboring clusters (to give repetitive global Ca(2+) spikes). We use total internal reflection fluorescence microscopy of two mammalian cell lines to define the temporal relationships between Ca(2+) puffs (interpuff intervals, IPI) and Ca(2+) spikes (interspike intervals) evoked by flash photolysis of caged IP(3). We find that IPI are much shorter than interspike intervals, that puff activity is stochastic with a recovery time that is much shorter than the refractory period of the cell, and that IPI are not periodic. We conclude that Ca(2+) spikes do not arise from oscillatory dynamics of IP(3)R clusters, but that repetitive Ca(2+) spiking with its longer timescales is an emergent property of the dynamics of the whole cluster array.
Modeling IP3induced Ca2+signaling based on its interspike interval statistics
bioRxiv (Cold Spring Harbor Laboratory), 2022
Inositol 1,4,5-trisphosphate (IP3) induced Ca 2+ signaling is a second messenger system used by almost all eukaryotic cells. Recent research identified 8 general properties of Ca 2+ spiking common to all cell types investigated and demonstrated randomness of Ca 2+ signaling on all structural levels. We suggest a theory of Ca 2+ spiking starting from the random behaviour of IP3 receptor channel clusters mediating the release of Ca 2+ from the endoplasmic reticulum. Spike generation begins after the absolute refractory period of the previous spike. According to its hierarchical spreading from initiating channel openings to cell level, we describe it as a first passage process from none to all clusters open while the cell recovers from the inhibition which terminated the previous spike. Our theory reproduces quantitatively all general properties for different IP3 pathways including the exponential stimulation response relation of the average interspike interval (ISI) Tav and its robustness properties, random spike timing with a linear moment relation between Tav and the ISI standard deviation and its robustness properties, sensitive dependency of Tav on diffusion properties, and non-oscillatory local dynamics. We explain large cell variability of Tav observed in experiments by variability of channel cluster coupling by Ca 2+ induced Ca 2+ release, the number of clusters and IP3 pathway components expression levels. We predict the relation between puff probability and agonist concentration, and [IP3] and agonist concentration. Differences of spike behaviour between cell types and stimulating agonists are explained by the different types of negative feedback terminating spikes. In summary, the hierarchical random character of spike generation explains all of the identified general properties.
Analysis of IP 3 receptors in and out of cells
Biochimica Et Biophysica Acta-general Subjects
Background: Inositol 1,4,5-trisphosphate receptors (IP 3 R) are expressed in almost all animal cells. Three mammalian genes encode closely related IP 3 R subunits, which assemble into homo-or hetero-tetramers to form intracellular Ca 2 + channels. Scope of the review: In this brief review, we first consider a variety of complementary methods that allow the links between IP 3 binding and channel gating to be defined. How does IP 3 binding to the IP 3 -binding core in each IP 3 R subunit cause opening of a cation-selective pore formed by residues towards the C-terminal? We then describe methods that allow IP 3 , Ca 2 + signals and IP 3 R mobility to be examined in intact cells. A final section briefly considers genetic analyses of IP 3 R signalling. Major conclusions: All IP 3 R are regulated by both IP 3 and Ca 2 + . This allows them to initiate and regeneratively propagate intracellular Ca 2 + signals. The elementary Ca 2 + release events evoked by IP 3 in intact cells are mediated by very small numbers of active IP 3 R and the Ca 2 + -mediated interactions between them. The spatial organization of these Ca 2 + signals and their stochastic dependence on so few IP 3 Rs highlight the need for methods that allow the spatial organization of IP 3 R signalling to be addressed with single-molecule resolution. General significance: A variety of complementary methods provide insight into the structural basis of IP 3 R activation and the contributions of IP 3 -evoked Ca 2 + signals to cellular physiology. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling.
Calcium signalling: How do IP3 receptors work?
Current Biology, 1997
The intracellular receptor for inositol 1,4,5trisphosphate (IP 3) is responsible for generation and control of very complex Ca 2+ signals. New experimental approaches to studying the kinetics of the IP 3 receptor are now beginning to give some insight into the mechanisms behind its rather bizarre properties.
Cell Calcium, 2015
Many intracellular Ca 2+ signals involve Ca 2+ release from the endoplasmic reticulum through inositol 1,4,5-trisphosphate receptors (IP 3 Rs). The open probability of IP 3 Rs depends on cytosolic Ca 2+ so that these signals involve Ca 2+ -induced Ca 2+ -release (CICR). IP 3 Rs are organized in clusters. The signals they mediate are observed using single-wavelength dyes and, often, a slow Ca 2+ buffer (EGTA) is added to disrupt CICR between clusters and keep the signals spatially restricted. It is assumed that the presence of the dye or of EGTA does not alter the intra-cluster Ca 2+ dynamics. In this paper we analyze this issue combining experiments and numerical simulations. We compare the properties of local signals known as puffs observed with different dyes and EGTA concentrations. We determine that although the dye or EGTA does not alter the intra-cluster dynamics, the set of observable events is different depending on the degree of inter-cluster uncoupling of the experiment. An analysis of the observations shows that the events that are missed for insufficient inter-cluster uncoupling are those of fastest amplitude growth rate. This agrees with a spatial organization in which the largest amplitude events correspond to clusters with densely packed active IP 3 Rs.
Calcium signalling: Ringing changes to the ‘bell-shaped curve’
Current Biology, 1999
The 'bell-shaped' curve relating cytosolic Ca 2+ concentration to IP 3 receptor activation is considered important in the generation of the complex Ca 2+ signals seen inside many cells. But recent findings suggest this bimodal relationship is not always evident and may not apply to some IP 3 receptor isoforms.