Cells Against High Concentration Gradients

Most body cells import glucose from the blood down its concentration gradient, utilizing one or another GLUT protein to facilitate this transport. However, certain cells, such as those lining the small intestine and the kidney tubules, need to import glucose from the intestinal lumen or forming urine against a very large concentration gradient. Such cells utilize a two-Na+/one-glucose symporter, a protein that couples import of one glucose molecule to the import of two Na+ ions:

2 Na"

glucoseo

2 Na"

glucose(I

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

[glucoseout]

Thus the AG 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). At equilibrium AG = 0. As illustrated in Figure 7-20, the free energy released by movement of Na+ into mammalian cells down its electrochemical gradient has a free-energy change AG of about —3 kcal per mole of Na+ transported. Thus the AG for transport of two moles of Na+ inward is about —6 kcal. By substituting this value into Equation 7-7 and setting AG = 0, we see that

[glucoseout]

and we can calculate that at equilibrium the ratio glucosein/ glucoseout = «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 (AG of —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, the two-Na+/one-glucose symporter permits cells to accumulate a very high concentration of glucose relative to the external concentration.

The two-Na+/glucose symporter is thought to contain 14 transmembrane a helices with both its N- and C-termini extending into the cytosol. A truncated recombinant protein consisting of only the five C-terminal transmembrane a helices can transport glucose independently of Na+ across the plasma membrane, down its concentration gradient. This portion of the molecule thus functions as a glucose uniporter. The N-terminal portion of the protein, including helices 1-9, is required to couple Na+ binding and influx to the transport of glucose against a concentration gradient.

Figure 7-21 depicts the current model of transport by Na+/glucose symporters. This model entails conformational changes in the protein analogous to those that occur in uniport transporters, such as GLUT1, which do not require a cotransported ion (see Figure 7-4). Binding of all substrates to their sites on the extracellular domain is required before out

Exterior

Exterior

Glucose

Cytosol

Glucose

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