Cui, Kaandorp, 2006

Model Status

This model has been curated and is known to run in PCEnv and COR. This version is able to reproduce figures from the original publication, although some tweeking of variables is required to produce the full range of figures. The model is currently parameterised to reproduce Fig 2a.

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Model Structure

In eukaryotic cells calcium functions as a ubiquitous intracellular messenger, capable of translating extracellular influences into physiological responses such as muscle contraction or cell division. In yeast cells (Saccharomyces cerevisiae a steady cytosolic calcium concentration is maintained within the range of 50-200 nM. The mechanisms underlying this calcium homeostasis involve the transfer and storage of calcium in various different intracellular compartments, including the vacuoles, endoplasmic reticulum (ER) and the Golgi apparatus, via membrane transport proteins, including pumps and channels.

Under normal conditions, extracellular calcium enters the cytosol through an unknown Channel X (yet to be identified). Cytosolic calcium can be then pumped into the ER and Golgi through a membrane protein called Pmrlp, and into the vacuole via two membrane proteins called Pmc1p and Vcx1p. Under the abnormal condition of extracellular hypertonic shock, the vacuoles can release calcium into cytosol through Yvclp. Expression of the genes for these three membrane proteins, namely Pmc1, Pmr1 and Vcx1, is regulated by calcineurin, which in turn is activated by a calcium-calmodulin complex. Calmodulin is a cytosolic calcium-binding protein which in its bound form can activate target proteins such as calcineurin. Activated calcineurin dephosphorylates the transcription factor Crz1p, promoting its translocation into the nucleus where it regulates the transcription of genes such as Pmc1 and Pmr1.

Although it is known that plant cells can secrete excess cytosolic calcium into the extracellular matrix through plasma membrane pumps and exchangers, no such membrane proteins have been identified in yeast cells. Never the less, calcium efflux from yeast cells has been observed, and it's believed that this occurs through exocytosis: Ca²⁺ in the ER/Golgi is packaged within secretory vesicles which will diffuse through the cytosol and will fuse with the plasma membrane to release their contents into the environment.

In their 2006 paper, Jiangjun Cui and Jaap Kaandorp present the first preliminary mathematical model of calcium homeostasis in yeast cells (see the figure below). The model parameters are based on experimental data, and it is hoped the results from model simulations will be used to inform the design of future experiments, will the ultimate aim of improving our understanding of the mechanisms underlying calcium homeostasis.

The complete original paper reference is cited below:

Mathematical modeling of calcium homeostasis in yeast cells, Jiangjun Cui and Jaap A. Kaandorp, 2006, Cell Calcium , 39, 337-348. PubMed ID: 16445978

A simplified diagram of the calcium fluxes described by the mathematical model. Extracellular calcium enters the cell cytosol through an unknown Channel X and also, under certain conditions such as depletion of secretory calcium, through the channel Cch1p-Mid1p. Cytosolic calcium can be pumped into the ER and Golgi through Pmrlp and into the vacuole through Pmc1p and Vcx1p. Under the abnormal condition of extracellular hypertonic shock, the vacuoles can release calcium into cytosol through Yvclp. Cytosolic calmodulin is a calcium-binding protein which in its bound form can activate target proteins such as calcineurin. Activated calcineurin dephosphorylates the transcription factor Crz1p, promoting its translocation into the nucleus where it regulates the transcription of genes such as Pmr1 and Pmc1.