5.12: Secondary Active Transport

One example of how cells use the energy contained in electrochemical gradients is demonstrated by glucose transport into cells. The ion vital to this process is sodium (Na⁺), which is typically present in higher concentrations extracellularly than in the cytosol. Such a concentration difference is due, in part, to the action of an enzyme “pump” embedded in the cellular membrane that actively expels Na⁺ from a cell. Importantly, as this pump contributes to the high concentration of positively-charged Na⁺ outside a cell, it also helps to make this environment “more positive” than the intracellular region. As a result, both the chemical and electrical gradients of Na⁺ point towards the inside of a cell, and the electrochemical gradient is similarly directed inwards.

Sodium-glucose Cotransporters

Sodium-glucose cotransporters (SGLTs) exploit the energy stored in this electrochemical gradient. These proteins, primarily located in the membranes of intestinal or kidney cells, help in the absorption of glucose from the lumen of these organs into the bloodstream. In order to function, both an extracellular glucose molecule and two Na⁺ must bind to the SGLT. As Na⁺ migrates into a cell through the transporter, it travels with its electrochemical gradient, expelling energy that the protein uses to move glucose inside a cell—against its chemical gradient, since this sugar tends to be at a higher concentration within a cell. As a result, glucose travels uphill against its concentration gradient simultaneously with Na⁺ that travels down its electrochemical gradient. This is an example of secondary active transport, so-named because the energy source used is electrochemical in nature, rather than the primary form of ATP.

Therapies Targeting SGLTs

Given the role of glucose in certain diseases, scientists have begun to look at ways of interfering with glucose transport into cells. For example, diabetes is characterized by excess glucose in the bloodstream, which can lead to nerve damage and other complications. As a result, some researchers are assessing how SGLT expression differs between diabetics and non-diabetics, and whether inhibiting different SGLTs can help treat the disease. Alternatively, since cancer cells have been demonstrated to require more glucose compared to their normal counterparts, other investigators are examining whether glucose transporters can be a new target of anti-cancer therapies.

Although primary and secondary active transport both rely on cell membrane proteins, the latter utilizes energy stored in ions' electrochemical gradients, not ATP, to power these proteins and shift molecules, like glucose, into cells, against gradients.

One protein that exemplifies secondary active transport is Sodium-Glucose Cotransporter 1. Initially, this transporter is positioned so that the cytoplasm facing side is closed, but the extracellular end is open. This exposes two negatively charged sodium binding sites to the environment, which are then bound by positively charged sodium ions.

Since more sodium ions populate the extracellular space than the cytoplasm, and the cell's interior is more negative, compared to its environment, the transporter-bound sodium ions are moving down their electrochemical gradient.

This releases energy, enabling the protein to change confirmation and increase its affinity for glucose, present at a low level outside but a high concentration inside the cell.

A glucose molecule then attaches to the transporter and this simultaneous binding of sodium and sugar causes the protein to close its extracellular region and open the cytoplasm facing side.

The sodium ions then detach and enter the cytoplasm. This decreases the protein's affinity for glucose and the sugar is subsequently released. It's cotransported with the ions into the cell but against its concentration gradient. Once empty, the transporter returns to its initial orientation.