Abstract
Kinetic models have been employed to understand the logic of substrate transport through transporters of the Solute Carrier (SLC) family. All SLC transporters operate according to the alternate access model, which posits that substrate transport occurs in a closed loop of partial reactions (i.e., a transport cycle). Kinetic models can help to find realistic estimates for conformational transitions between individual states of the transport cycle. When constrained by experimental results, kinetic models can faithfully describe the function of a candidate transporter at a pre-steady state. In addition, we show that kinetic models can accurately predict the intra- and extracellular substrate concentrations maintained by the transporter at a steady state, even under the premise of loose coupling between the electrochemical gradient of the driving ion and of the substrate. We define the criteria for the design of a credible kinetic model of the SLC transporter. Parsimony is the guiding principle of kinetic modeling. We argue, however, that the level of acceptable parsimony is limited by the need to account for the substrate gradient established by a secondary active transporter, and for random order binding of co-substrates and substrate. Random order binding has consistently been observed in transporters of the SLC group.
Highlights
Biological membranes are diffusion barriers for polar solutes
The generalized equation for the electrochemical potential of secondary active transporters (Figure 1A) allows for calculating the intraand extracellular substrate concentrations maintained by a transporter at the steady state, given that the transport stoichiometry, the intra- and extracellular ion concentrations, and the membrane potential, are known
What is striking are the factors which are not included in the equation, and which have no influence upon the substrate concentrations at the steady state
Summary
The solute carrier (SLC) group of membrane proteins allows for the passage of polar solutes across the cell surface membranes and through intracellular membranes [1]. The solute carrier proteins include examples of transporters, which by lowering the membrane-imposed diffusion barrier, facilitate the downhill flow of solutes along their electrochemical gradient, i.e., facilitating transporters. The other type of membrane transporters in the SLC group are secondary active transporters These lower the diffusion barrier for polar solutes, but in addition allow solutes to flow uphill against their electrochemical gradient by coupling their transport to the gradient of a second solute [5]. Secondary active transporters can operate in two ways: In symporters, the vectorial transport of substrate and co-substrate is in the same direction; in antiporters, the substrate and co-substrate are counter-transported
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