BG_GPCR_M2_reduced
About this model
This is a bond-graph model of the metabolism of the G-protein coupled receptor (muscarinic acetylcholine M2 receptor, R) and the associated Gi protein in the cardiac cell.
- INPUTS:
- Ligand (L) stimulus e.g. metacholine
- OUTPUTS:
- Change in molar amount of GiαGTP
- REACTIONS:
- Rswitch: Spontaneous activation of R from an inactivate state to a state that can bind a Gi protein
- LRswitch: Similar to Rswitch, but with substrate of inactive complex LR
- RL: the binding of L to R
- RC: the binding of Gi to R
- RR: the binding of Gi to complex LR
- Act1: Bundled reactions representing the transient exchange of GDP for GTP on the active RG complex, which forms GiαGTP, Giβγ, GDP and Rtag. The latter is the R protein tagged for internalisation
- Act2: Similar to Act1, but with substrate LRG and product LRtag
- Hyd: Hydrolysis of GTP on Giα GTP, forming GiαGDP and phosphate
- Reassoc: Binding of GiαGDP and Giβγ to reform Gi
- InternR: Internalisation of Rtag by the GRK and arrestin proteins
- InternLR: Similar to InternR, but for substrate LR 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.
Fig. 1. Bond-graph formulation of the GPCR-M2 network
| Abbreviation | Name |
|---|---|
| Gi | Gi protein |
| Giα | Alpha subunit of the Gi protein |
| Giβγ | Beta and gamma subunits of the Gi protein |
| GDP | Guanosine diphosphate |
| GRK | G protein-coupled receptor kinase |
| GTP | Guanosine triphosphate |
| L | Ligand |
| Pi | Phosphate |
| R | Receptor (muscarinic acetylcholine receptor) |
| Ri | Receptor (inactive form) |
| Rtag | 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, which relies on the:
- stoichiometry of system
- kinetic constants for forward/reverse reactions
- If not already, all reactions are made reversible by assigning a small value to the reverse direction.
Here, this solve process is performed in Python.
Original kinetic model
Saucerman et al: Modeling beta-adrenergic control of cardiac myocyte contractility in silico.
Additional detail on receptor internalisation were provided by Stephen Duffull et al. (University of Otago).