Since the plasma membrane of the neuron is highly permeable to K⁺ and slightly permeable to Na⁺, and since neither of these ions is in a state of equilibrium (Na⁺ being at higher concentration outside the cell than inside and K⁺ at higher concentration inside the cell), then a natural occurrence should be the diffusion of both ions down their electrochemical gradients—K⁺ out of the cell and Na⁺ into the cell. However, the concentrations of these ions are maintained at constant disequilibrium, indicating that there is a compensatory mechanism moving Na⁺ outward against its concentration gradient and K⁺ inward. This mechanism is the sodium-potassium pump. Actually a large protein molecule that traverses the plasma membrane of the neuron, the pump presents receptor areas to both the cytoplasm and the extracellular environment. That part of the molecule facing the cytoplasm has a high affinity for Na⁺ and a low affinity for K⁺, while that part facing the outside has a high affinity for K⁺ and a low affinity for Na⁺. Stimulated by the action of the ions on its receptors, the pump transports them in opposite directions against their concentration gradients.

If equal amounts of Na⁺ and K⁺ were transported across the membrane by the pump, the net charge transfer would be zero; there would be no net flow of current and no effect on the membrane potential. In fact, in many neurons three sodium ions are transported for every potassium ion; sometimes the ratio is three sodium ions for every two potassium ions, and in a few neurons it is two sodium ions for one potassium ion. This inequality of ionic transfer produces a net efflux of positive charge, maintaining a polarized membrane with the inner surface slightly negative in relation to the outer surface. Because it creates this potential difference across the membrane, the sodium-potassium pump is said to be electrogenic.

The sodium-potassium pump carries out a form of active transport—that is, its pumping of ions against their gradients requires the addition of energy from an outside source. That source is adenosine triphosphate (ATP), the principal energy-carrying molecule of the cell. ATP is formed by an inorganic phosphate molecule held in high-energy linkage with a molecule of adenosine diphosphate (ADP). When an enzyme in the pump, called sodium-potassium-ATPase, splits the phosphate from the ADP, the energy released powers the transport action of the pump.

Passive transport: membrane channels

The sodium-potassium pump sets the membrane potential of the neuron by keeping the concentrations of Na⁺ and K⁺ at constant disequilibrium. The sudden shift from a resting to an active state, when the neuron generates a nerve impulse, is caused by a sudden movement of ions across the membrane—specifically, a flux of Na⁺ into the cell. Given the relative impermeability of the plasma membrane to Na⁺, this influx itself implies a sudden change in permeability. Beginning in the 19th century, researchers puzzled over the mechanism by which this change could occur. The idea arose that there must exist pores, or channels, through which the ions could diffuse, passing the barrier posed by the lipid bilayer. However, for years only the gross currents accompanying ionic movement could be measured, and it was only by inference that the presence of membrane channels could be postulated.

The breakthrough came in the 1970s and ’80s with the development of the patch-clamp technique, which enabled researchers to directly measure currents flowing across single ion channels in the membrane. The patch-clamp technique electrically isolates a small patch of neuron or muscle cell membrane by applying the tip of a micropipette filled with conducting solution to the membrane and forming a tight seal with it. As single channels in the patch undergo various transitional states between fully open and fully closed, the times of opening and closing are recorded and the amplitudes and duration of the currents are measured.

Since the pioneering studies, the electrical and biochemical properties of certain channels have been characterized. Known as “voltage dependent” when activated by changes in the membrane potential and “neurotransmitter sensitive” when activated by neurotransmitter substances, these channels are protein structures that span the membrane from the extracellular space to the cytoplasm. They are thought to be cylindrical, with a hollow, water-filled pore wider than the ion passing through it except at one region called the selectivity filter. This filter makes each channel specific to one type of ion.