Of these various transporters, the best understood is the Na⁺/K⁺ pump. The activity of this pump is estimated to account for 20–40% of the brain's energy consumption, indicating its importance for brain function. The Na⁺ pump was first discovered in neurons in the 1950s, when Richard Keynes at Cambridge University used radioactive Na⁺ to demonstrate the energy-dependent efflux of Na⁺ from squid giant axons. Keynes and his collaborators found that this efflux ceased when the supply of ATP in the axon was interrupted by treatment with metabolic poisons (Figure 4.10A, point 4). Other conditions that lower intracellular ATP also prevent Na⁺ efflux. These experiments showed that removing intracellular Na⁺ requires cellular metabolism. Further studies with radioactive K⁺ demonstrated that Na⁺ efflux is associated with simultaneous, ATP-dependent influx of K⁺. These opposing fluxes of Na⁺ and K⁺ are operationally inseparable: Removal of external K⁺ greatly reduces Na⁺ efflux (Figure 4.10, point 2) and vice versa. These energy-dependent movements of Na⁺ and K⁺ implicated an ATP-hydrolyzing Na⁺/K⁺ pump in the generation of the transmembrane gradients of both Na⁺ and K⁺. The exact mechanism responsible for these fluxes of Na⁺ and K⁺ is still not entirely clear, but the pump is thought to alternately shuttle these ions across the membranes in a cycle fueled by the transfer of a phosphate group from ATP to the pump protein (Figure 4.10B).

Figure 4.10

Ionic movements due to the Na⁺/K⁺ pump. (A) Measurement of radioactive Na⁺ efflux from a squid giant axon. This efflux depends on external K⁺ and intracellular ATP. (B) A model for the movement of ions by the Na⁺/K⁺ pump. Uphill movements of Na⁺ and K (more...)

Additional quantitative studies of the movements of Na⁺ and K⁺ indicate that the two ions are not pumped at identical rates: The K⁺ influx is only about two-thirds the Na⁺ efflux. Thus, the pump apparently transports two K⁺ into the cell for every three Na⁺ that are removed (see Figure 4.10B). This stoichiometry causes a net loss of one positively charged ion from inside of the cell during each round of pumping, meaning that the pump generates an electrical current that can hyperpolarize the membrane potential. For this reason, the Na⁺/K⁺ pump is said to be electrogenic. Because pumps act much more slowly than ion channels, the current produced by the Na⁺/K⁺ pump is quite small. For example, in the squid axon, the net current generated by the pump is less than 1% of the current flowing through voltage-gated Na⁺ channels and affects the resting membrane potential by only a millivolt or less.

Although the electrical current generated by the activity of the Na⁺/K⁺ pump is small, under special circumstances the pump can significantly influence the membrane potential. For instance, prolonged stimulation of small unmyelinated axons produces a substantial hyperpolarization (Figure 4.11). During the period of stimulation, Na⁺ enters through voltage-gated channels and accumulates within the axons. As the pump removes this extra Na⁺, the resulting current generates a long-lasting hyperpolarization. Support for this interpretation comes from the observation that conditions that block the Na⁺/K⁺ pump—for example, treatment with ouabain, a plant glycoside that specifically inhibits the pump—prevent the hyperpolarization. The electrical contribution of the Na⁺/K⁺ pump is particularly significant in these small-diameter axons because their large surface-to-volume ratio causes intracellular Na⁺ concentration to rise to higher levels than it would in other cells. Nonetheless, it is important to emphasize that, in most circumstances, the Na⁺/K⁺ pump plays no part in generating the action potential and has very little direct effect on the resting potential.

Figure 4.11

The electrogenic transport of ions by the Na⁺/K⁺ pump can influence membrane potential. Measurements of the membrane potential of a small unmyelinated axon show that a train of action potentials is followed by a long-lasting hyperpolarization. This hyperpolarization (more...)