A kinetic model of the thiazide-sensitive Na-Cl cotransporter
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This CellML model runs in OpenCell and COR. The units have ben checked and they are consistent. We are unsure whether or not the model recreates the published results as there are no simple figures of changing concentration against time. Also sodium and chloride are set to constant values in this model - we suspect we need to derive an ODE equation based on the reaction figure (fig 1) in the paper.
Model Structure
ABSTRACT: The aim of this study was to construct a numerical model of the thiazide-sensitive Na-Cl cotransporter (TSC) that can predict kinetics of thiazide binding and substrate transport of TSC. We hypothesized that the mechanisms underlying these kinetic properties can be approximated by a state diagram in which the transporter has two binding sites, one for sodium and another for chloride and thiazide. On the basis of the state diagram, a system of linear equations that should be satisfied in the steady state was postulated. Numerical solution of these equations yielded model prediction of kinetics of thiazide binding and substrate transport. Rate constants, which determine transitional rates between states, were systematically adjusted to minimize a penalty function that was devised to quantitatively estimate the difference between model predictions and experimental results. With the resultant rate constants, the model could simulate the following experimental results: 1) dissociation constant of thiazide in the absence of sodium and chloride; 2) inhibitory effect of chloride on thiazide binding; 3) stimulatory effect of sodium on thiazide binding; 4) combined effects of sodium and chloride on thiazide binding; 5) dependence of sodium influx on extracellular sodium and chloride; and 6) inhibition of sodium influx by extracellular thiazide. We conclude that known kinetic properties of TSC can be predicted by a model which is based on a state diagram.
The original paper reference is cited below:
A kinetic model of the thiazide-sensitive Na-Cl cotransporter, Hangil Chang and Toshiro Fujita, 1999,
American Journal of Physiology, 276, F952-F959. PubMed ID: 10362783
diagram of the model
State diagram for the thiazide-sensitive Na-Cl cotransporter (TSC). Transporter (E) has binding sites for sodium (Na ) and chloride (Cl). Thiazide diuretics (D) compete with chloride for the same binding site. _i is used to indicate which symbols belong to the intracellular side.
kidney
electrophysiology
Intracellular Transporter-Sodium-Chloride Complex
ENaCl_i
The University of Auckland, Auckland Bioengineering Institute
Extracellular Transporter
E
Intracellular Transporter
E_
Extracellular Transporter-Thiazide Diuretics Complex
ED
Hangil
Chang
Intracellular Transporter-Sodium Complex
ENa_
Extracellular Transporter-Sodium-Chloride Complex
ENaCl
2007-06-05T09:16:58+12:00
2007-06-25T13:20:00+12:00
Catherine
Lloyd
May
keyword
Extracellular Transporter-Chloride Complex
ECl
This is the CellML description of Chang and Fujita's 1999 kinetic model of the thiazide-sensitive Na-Cl cotransporter of the renal distal tubule. This model can be run in PCEnv but it gives a flat output. I suspect it needs to be embedded within a whole cell model in order to give a reasonable output.
The University of Auckland
Auckland Bioengineering Institute
Chang and Fujita's 1999 kinetic model of the thiazide-sensitive Na-Cl cotransporter of the renal distal tubule.
Renal Distal Tubule
Intracellular Transporter-Chloride Complex
ECl_
Catherine Lloyd
American Journal of Physiology
Extracellular Transporter-Sodium Complex
ENa
Catherine
Lloyd
May
The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
The model runs in the PCEnv simulator but gives a flat output.
Intracellular Transporter-Thiazide Diuretics Complex
ED_
Extracellular Transporter-Thiazide Diuretics-Sodium Complex
ENaD
The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
c.lloyd@auckland.ac.nz
10362783
Toshiro
Fujita
Intracellular Transporter-Thiazide Diuretics-Sodium Complex
ENaD_
Removed reaction element and replaced with simple MathML
1999-06
2007-05-28T00:00:00+00:00
A kinetic model of the thiazide-sensitive Na-Cl cotransporter
276
F952
F959
Catherine Lloyd