- Author:
- Shelley Fong <s.fong@auckland.ac.nz>
- Date:
- 2022-02-18 13:27:41+13:00
- Desc:
- Updating way cellml is written
- Permanent Source URI:
- https://models.physiomeproject.org/workspace/7dc/rawfile/27738c8bd7e535b72ec3ad5073fc326dd3e96855/exposure/exposure_frontpage.rst
About this model
====================
This is a bond-graph model of the metabolism of the G-protein coupled receptor (:math:`{\beta}`-1 adrenergic receptor, R) and the associated Gs protein in the cardiac cell.
**INPUTS:**
- Ligand (L) stimulus e.g. isoproterenol
**OUTPUTS:**
- Change in molar amount of Gs\ :math:`{\alpha}`\ :sub:`GTP`\
**REACTIONS:**
- R\ :sub:`switch`\ : Spontaneous activation of R from an inactivate state to a state that can bind a Gs protein
- LR\ :sub:`switch`\ : Similar to R\ :sub:`switch`\ , but with substrate of inactive complex LR
- R\ :sub:`L`\ : the binding of L to R
- R\ :sub:`C`\ : the binding of Gs to R
- R\ :sub:`R`\ : the binding of Gs to complex LR
- Act1: Bundled reactions representing the transient exchange of GDP for GTP on the active RG complex, which forms Gs\ :math:`{\alpha}`\ :sub:`GTP`\, Gs\ :math:`{\beta\gamma}`, GDP and R\ :sub:`tag`\. The latter is the R protein tagged for internalisation
- Act2: Similar to Act1, but with substrate LRG and product LR\ :sub:`tag`\
- Hyd: Hydration of GTP on Gs\ :math:`{\alpha}` :sub:`GTP`\, forming Gs\ :math:`{\alpha}`\ :sub:`GDP` and phosphate
- Reassoc: Binding of Gs\ :math:`{\alpha}`\ :sub:`GDP` and Gs\ :math:`{\beta\gamma}` to reform Gs
- Intern\ :sub:`R`\ : Internalisation of R\ :sub:`tag` by the GRK and arrestin proteins
- Intern\ :sub:`LR`\ : Similar to Intern\ :sub:`R`\, but for substrate LR :sub:`tag`\
Model status
=============
The current CellML implementation runs in OpenCOR.
Model overview
===================
This model is based on 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.
For the following figures, all enzymes are shown in maroon.
.. figure:: exposure/BG_GPCR_B1AR.png
:width: 100%
:align: center
:alt: BG PKACI reaction
Fig. 1. Bond-graph formulation of the GPCR-\ :math:`{\beta}`\ 1AR 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
"Gs", "Gs protein"
"Gs\ :math:`{\alpha}`\", "Alpha subunit of the Gs protein"
"Gs\ :math:`{\beta\gamma}`\", "Beta and gamma subunits of the Gs protein"
"GDP", "Guanosine diphosphate"
"GRK", "G protein-coupled receptor kinase"
"GTP", "Guanosine triphosphate"
"L", "Ligand"
"P\ :sub:`i`", "Phosphate"
"R", "Receptor (:math:`{\beta}`-1 adrenergic receptor)"
"R\ :sub:`i`", "Receptor (inactive form)"
"R\ :sub:`tag`", "Receptor tagged for internalisation by GRK"
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/7dc/rawfile/29d84125387d3b09137c8a01e76721eda14cae33/parameter_finder/kinetic_parameters_GPCR_B1AR_reduced.py>`_.
Here, this solve process is performed in Python.
Original kinetic model
======================
Saucerman et al: `Modeling beta-adrenergic control of cardiac myocyte contractility in silico. <https://models.physiomeproject.org/exposure/9766d9bd0325c31e47a31b291e26ccad>`_
Additional detail on receptor internalisation were provided by Stephen Duffull et al. (University of Otago).
