A kinetic model of the thiazide-sensitive Na-Cl cotransporter.
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.
Chang
H
H
Health Service Center, University of Tokyo, Tokyo 153-8902, Japan.
Fujita
T
T
D001581:Benzothiadiazines; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism / Q000494:pharmacology; D004232:Diuretics; D005110:Extracellular Space / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D049992:Sodium Chloride Symporters; D027981:Symporters
D001581:Benzothiadiazines; D002352:Carrier Proteins; D002712:Chlorides; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D049992:Sodium Chloride Symporters; D027981:Symporters; D012964:Sodium