Rate control within the Na+/glucose cotransporter

The intestinal Na+/glucose cotransporter has recently been cloned and expressed in Xenopus oocytes, and kinetically characterised to produce a 6-state model of the transporter. We have analyzed this model using control analysis to determine the extent to which each rate constant and step in the mechanism limits the steady-state rates under various conditions. We show that control (rate limitation) is distributed among a number of rate constants and changes with the membrane potential and the concentrations of external and internal sodium and sugar. There is no single rate-limiting step but, with saturating concentrations of external sugar and sodium and negligible internal concentrations, the sugar and sodium fluxes are limited by sodium dissociation on the inside, translocation of the unloaded carrier to the outside and translocation of the fully loaded carrier to the inside. With more physiological external and internal concentrations there is a significant leak flux, which causes the cotransporter to act as a sugar uniporter, and entails that control over the sugar flux differs from control over the sodium flux. In these conditions control is widely distributed among many of the rate constants. The analysis shows that the concept of a rate-limiting step is not generally applicable to transporters.