Most body cells import glucose from the blood down a concentration gradient of glucose, using GLUT proteins to facilitate this transport. However, certain cells, such as those lining the small intestine and the kidney tubules, need to import glucose from extracellular fluids (digestive products or urine) against a very large concentration gradient (glucose concentration is higher inside the cell). Such cells use a two-Na⁺/one-glucose symporter, a protein that couples the import of one glucose molecule to the import of two Na⁺ ions:

2 Na⁺_out + glucose_out ⇌ 2 Na⁺_in + glucose_in

Quantitatively, the free-energy change for the symport of two Na⁺ ions and one glucose molecule can be written

Thus the ΔG for the overall reaction is the sum of the free-energy changes generated by the glucose concentration gradient (1 molecule transported), the Na⁺ concentration gradient (2 Na⁺ ions transported), and the membrane potential (2 Na⁺ ions transported). As illustrated in Figure 11-25, the movement of Na⁺ ions into a mammalian cell down their electrochemical gradient has a free-energy change, ΔG, of about −3 kcal per mole of Na⁺ transported. Thus the ΔG for the transport of two moles of Na⁺ inward would be twice this amount, or about −6 kcal. This negative free-energy change for sodium import is coupled to the uphill transport of glucose, a process with a positive ΔG. We can calculate the glucose concentration gradient (inside greater than outside) that can be established by the action of this Na⁺-powered symporter by realizing that at equilibrium for Na⁺-linked glucose import, ΔG = 0. By substituting the values for sodium import into Equation 11-7 and setting ΔG = 0, we see that

and we can calculate that at equilibrium, the ratio of glucose_in/glucose_out = ~30,000. Thus the inward flow of two moles of Na⁺ can generate an intracellular glucose concentration that is ~30,000 times greater than the exterior concentration. If only one Na⁺ ion were imported (ΔG of approximately −3 kcal/mol) per glucose molecule, then the available energy could generate a glucose concentration gradient (inside/outside) of only about 170-fold. Thus by coupling the transport of two Na⁺ ions to the transport of one glucose molecule, the two-Na⁺/one-glucose symporter permits cells to accumulate a very high concentration of glucose relative to the external concentration. This means that glucose that is present even at very low concentrations in the lumen of the intestine or in the kidney tubules can be efficiently transported into the lining cells and not lost from the body.

The two-Na⁺/one-glucose symporter is thought to contain 14 transmembrane α helices with both its N- and C-termini extending into the cytosol. Figure 11-26 depicts the current model of transport by Na⁺/glucose symporters. This model entails conformational changes in the protein analogous to those that occur in uniporters, such as GLUT1, that do not require a cotransported ion (compare with Figure 11-5). Binding of all substrates to their sites on the extracellular domain is required before the protein undergoes the change that converts the substrate-binding sites from the outward- to the inward-facing conformation; this ensures that inward transport of glucose and Na⁺ ions are coupled.

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