- Author:
- Shelley Fong <s.fong@auckland.ac.nz>
- Date:
- 2022-02-18 09:51:41+13:00
- Desc:
- Updating way cellml is written
- Permanent Source URI:
- https://models.cellml.org/workspace/674/rawfile/c68eb6e8bb923a34a47d383069914fe831c6e206/exposure/exposure_frontpage.rst
About this model
====================
This is a bond-graph model of cyclic AMP (cAMP) and adenylyl cyclase (AC) metabolism in the cardiac cell.
**INPUTS:**
- ATP stimulus
**OUTPUTS:**
- Change in molar amounts of AC, cAMP
**REACTIONS:**
- Re1: Conversion of ATP into cAMP via AC
- Re2: Conversion of ATP into cAMP via the activated alpha unit of the Gs protein bound by AC (Gs\ :math:`{\alpha}`\ :sub:`GTP`\:AC)
- Re3: Conversion of ATP into cAMP via the forskolin-AC complex (FSK:AC)
- Re4: Cleavage of cAMP into 5'AMP via a phosphodiesterase (PDE)
- Re5: Inhibition of PDE by IBMX
- Re6: Binding of Gs\ :math:`{\alpha}`\ :sub:`GTP`\ to AC
- Re7: Binding of FSK to AC
- Re8: Inhibition of AC by the activated alpha unit of the Gi protein (Gi\ :math:`{\alpha}`\ :sub:`GTP`\)
Model status
=============
The current CellML implementation runs in OpenCOR.
Model overview
===================
This model is made from an existing kinetic model, where the mathematics are translated into the bond-graph formalism. This describes the model in energetic terms and forces adherence to the laws of thermodynamics.
Most reactions follow Michaelis-Menten kinetics, where an intermediate complex is made before the final product is created (e.g. Re:1a and Re:1b). All other reactions (Re5-8) follow classical mass-action kinetics.
For the following figure, all enzymes of a given reaction are shown in maroon.
.. figure:: exposure/BG_cAMP_network.png
:width: 100%
:align: center
:alt: BG cAMP
Fig. 1. Bond-graph formulation of the cAMP network
|
For the above bond-graphs, a '0' node refers to a junction where all chemical potentials are the same. A '1' node refers to all fluxes being the same going in and out of the junction.
.. csv-table:: List of chemical species
:header: "Abbreviation", "Name"
:widths: 5, 15
"AC", "Adenylyl cyclase"
"AC\ :sub:`inh`\", "Inactivated variant of adenylyl cyclase"
"ATP", "Adenosine triphosphate"
"cAMP", "cyclic AMP"
"FSK", "forskolin"
"Gi\ :math:`{\alpha}`\", "alpha subunit of the Gi protein"
"Gs\ :math:`{\alpha}`\", "alpha subunit of the Gs protein"
"IBMX", "3-isobutyl-1-methylxanthine"
"PDE", "phosphodiesterase"
"PDE\ :sub:`inh`\", "Inactivated variant of phosphodiesterase"
"PPi", "pyrophosphate"
Parameter finding
~~~~~~~~~~~~~~~~~
A description of the process to find bond-graph parameters is shown in the folder `parameter_finder <parameter_finder>`_, which relies on the:
1. stoichiometry of system
2. kinetic constants for forward/reverse reactions
- If not already, all reactions are made reversible by assigning a small value to the reverse direction.
3. `linear algebra script <https://models.physiomeproject.org/workspace/674/file/b2070ffa54db6cc707aaa0feaeee5c7f5f9cda7e/parameter_finder/find_BG_parameters.py>`_.
Here, this solve process is performed in Python.
Original kinetic model
======================
This bond-graph network is largely based on cAMP metabolism of Saucerman et al: `Modeling beta-adrenergic control of cardiac myocyte contractility in silico. <https://models.physiomeproject.org/exposure/9766d9bd0325c31e47a31b291e26ccad>`_
