Simulating Complex Calcium-Calcineurin Signaling Network

Simulating Complex Calcium-Calcineurin Signaling Network

Model Status

This CellML model runs in both PCEnv and COR to recreate the published results. The units have been checked in COR and they are consistent.

ValidateCellML verifies this model as valid CellML but detects a unit inconsistency.

Model Structure

Calcium act as a ubiquitous messenger in eukaryotic cells, playing an essential role in a diverse range of processes including cell proliferation, muscle contraction, and apoptosis. Calcium also plays a key role in controlling the hypertrophic growth of the heart through a complex calcium-calcineurin-MCIP-NFAT signalling network (see the figure below). Cardiac hypertrophy is a thickening of the muscular wall of the heart in response to stresses such as physiological and pathological stimuli. Chronic cardiac hypertrophy may progress to heart failure, thus providing a huge incentive to better understand the signalling pathways and molecular mechansims underlying the pathogenesis. Computational modelling is likely to play an important role in analysing the quantitative behaviour of such pathways, in turn providing data for the basis of potential therapeutic drug design.

In a cardiac myocyte, stress to the cell can stimulate an influx of Ca2+ which, in turn, binds to calmodulin (CaM). The Ca2+-bound CaM then binds to calcineurin (CaN) to activate it. CaN* (activated CaN) can bind to modulatory calcineurin-interacting protein (MCIP) to form Complex1 and CaN* can also act as the enzyme to catalyse the dephosphorylation of NFATP into NFAT. The reverse reaction is catalysed by GSK3β (the conversion of NFAT into NFATP), which can bind to 14-3-3 to form Complex3. In addition to these cytosolic reactions, the enzyme-catalysed, reversible conversion between NFAT and NFATP can also occur in the nuclues of the cell. Cytosolic NFAT is imported into the nucleus, where it initiates the transcription of the hypertrophic genes and the gene encoding MCIP, and nuclear NFATP is exported into the cytosol. The enzymes catalysing the interconversion of NFAT and NFATP (GSK3β and CaN*) are also shuttled between the nucleus and the cytosol.

Under alternative stresses, such as pressure overload, big mitogen-activated protein kinase 1 (BMK1) becomes activated, leading to the phosphorylation of MCIP into MCIPp, which can be further phosphorylated to MCIPpp by GSK3β. The dephosphorylation of MCIPpp into MCIPp is again catalysed by CaN*. MCIPpp will bind with 14-3-3 to form Complex2, and MCIP1 seems to facilitate or suppress cardiac CaN signalling, dependent on the nature of the stress.

In 2006, Shin et al. published a paper which modelled the dual role of MCIP in cardiac hypertrophy. In the study described here, Cui and Kaandorp have extended this model to include more recent and extensive experimental data. They used Cellerator, an open source software, to automatically generate the equations, and the model was subsequently translated into CellML to facilitate future model exchange, reuse and implementation.

A schematic diagram of the Ca2+-calcineurin-MCIP-NFAT signalling networks in cardiac myocytes described by the model. Abbreviations: calmodulin (CaM); calcineurin (CaN); activated calcineurin (CaN*); nuclear factor of activated T-cells (NFAT); phosphorylated NFAT (NFATP); modulatory calcineurin-interacting protein (MCIP); phosphorylated MCIP on serine 112 (MCIPP); phosphorylated MCIP on both serine 112 and serine 108 (MCIPPP); big mitogen-activated protein kinase 1 (BMK1); glycogen synthase 3β (GSK3β); the complex formed by MCIP and calcineurin (Complex1); the complex formed by MCIPPP and 14-3-3 (Complex2); the complex formed by NFATP and 14-3-3 (Complex3); pressure overload (PO); hypertrophic stimuli (stress).

The complete original paper reference is cited below:

Simulating Complex Calcium-Calcineurin Signaling Network, Jiangjun Cui and Jaap A. Kaandorp, 2008, Lecture Notes in Computer Science , 5013, 110-119.