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Modeling the intracellular organization of calcium signaling

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Calcium (Ca2+) is a key signaling ion that plays a fundamental role in many cellular processes in most types of tissues and organisms. The versatility of this signaling pathway is remarkable. Depending on the cell type and the stimulus, intracellular Ca2+ increases can last over different periods, as short spikes or more sustained signals. From a spatial point of view, they can be localized or invade the whole cell. Such a richness of behaviors is possible thanks to numerous exchange processes with the external medium or internal Ca2+ pools, mainly the endoplasmic or sarcoplasmic reticulum and mitochondria. These fluxes are also highly regulated. In order to get an accurate description of the spatiotemporal organization of Ca2+ signaling, it is useful to resort to modeling. Thus, each flux can be described by an appropriate kinetic expression. Ca2+ dynamics in a given cell type can then be simulated by a modular approach, consisting of the assembly of computational descriptions of the appropriate fluxes and regulations. Modeling can also be used to get insight into the mechanisms of decoding of the Ca2+ signals responsible for cellular responses. Cells can use frequency or amplitude coding, as well as take profit of Ca2+ oscillations to increase their sensitivity to small average Ca2+ increases. This article is categorized under: Models of Systems Properties and Processes > Cellular Models Biological Mechanisms > Cell Signaling

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Schematic representation of the main intracellular processes playing an important role in Ca2+ homeostasis. Hormonal stimulation leads to the activation of the phospholipase C (PLC) that synthesizes inositol 1,4,5‐trisphosphate (InsP3). This messenger can be phosphorylated into InsP4 or dephosphorylated into InsP2. InsP3 binds to InsP3 receptors (IP3Rs) on the surface of the endoplasmic reticulum (ER) and thereby initiates Ca2+ release. Ca2+ can also be released from the ER through ryanodine receptors (RyRs). SERCA pumps are Ca2+ ATPases that actively transport Ca2+ from the cytosol into the ER. The filling state of the ER is sensed by STIM, the Ca2+‐unbound state of which can bind to Orai and thereby initiate the influx of Ca2+ from the extracellular medium into the cytosol. PMCAs are plasma membrane Ca2+ ATPases that actively transport Ca2+ from the cytosol into the extracellular medium. In the cytosol, and in the intracellular organelles, Ca2+ reversibly binds to Ca2+ buffers. Ca2+ exchanges between the cytosol and mitochondria are also important for cellular Ca2+ homeostasis. Ca2+ enters in mitochondria through the Ca2+ uniporter (UNI) and is released through the Na+/Ca2+ exchanger. Upon conditions of very high Ca2+ load, permeability transition pores (PTP) open thereby releasing Ca2+ as well as proapoptotic agents.
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Computational simulations of the Ca2+ exchanges between the cytosol and mitochondria during inositol 1,4,5‐trisphosphate (InsP3)‐induced Ca2+ oscillations. The model combines a classical description of InsP3‐mediated Ca2+ oscillations due to the biphasic regulation of the IP3R and the model of Fall and Keizer for mitochondria (see Ref ). As shown in the lower panel, Ca2+ increases (blue) in mitochondria lead to mitochondrial depolarization (red).
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Schematic representation of the main processes driving the Ca2+ exchanges between the cytoplasm and the mitochondria. Processes shown in red are part of mitochondrial metabolism and transform pyruvate into NADH that will feed the electron transport chain. Shown in blue are the proton fluxes: H+ is extruded by using the electrochemical energy provided by the electron transport chain, while the F0/F1 ATPase uses the energy provided by the proton gradient to phosphorylate ADP into ATP. Ca2+ enters and leaves mitochondria through the processes indicated in black. The proton and Ca2+ gradients across the mitochondrial membrane are responsible for the voltage difference between the outer and inner sides of mitochondria. (Reprinted with permission from Ref . Copyright 2001 Elsevier; Reprinted with permission from Ref . Copyright 2011 Elsevier).
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Schematic representation of the core model for mGlu5 receptor‐stimulated Ca2+ oscillations. Glutamate‐bound dimers of mGlu5 receptor activate phospholipase C (PLC) through Gαq/11 proteins that are not considered explicitly in the model. This results in an increase in inositol 1,4,5‐trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers Ca2+ release from the endoplasmic reticulum (ER). This process is regulated by cytosolic Ca2+, both positively and negatively. Cytosolic Ca2+ can be resequestered by the ER through a Ca2+ATPase (SERCA). DAG activates a protein kinase C of the novel PKC family, which phosphorylates the mGlu5 receptor. This phosphorylation uncouples the receptor from the transduction mechanism leading to PLC activation. As shown in the lower panel, this model accounts for the existence of oscillations in the concentration of cytosolic Ca2+ (blue curve) that are driven by changes in the phosphorylation status of mGluR5 (red curve).
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Biological Mechanisms > Cell Signaling
Models of Systems Properties and Processes > Cellular Models

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