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The cell membranes of neurons, like those of all other cells, are lipid bilayers that are impermeable to ions but contain many protein molecules that serve as *ion transporters and ion channels. Ion transporters and channels are responsible for the distribution of charges across the membrane that determine membrane potential.

Ion transporters require energy to move ions against their concentration or electrical gradients and are therefore called ion pumps. A major ion transporter in the cell membranes of neurons (and all other cells) is the sodium–potassium pump, so called because it actively expels Na⁺ ions from inside the cell, exchanging them for K⁺ ions from outside the cell (see Figure 6.14). The Na⁺–K⁺ pump is also known as sodium–potassium ATPase, a term emphasizing that it is an enzyme complex requiring ATP to do its work. The Na⁺–K⁺ pump keeps the concentration of K⁺ inside the cell greater than the K⁺ concentration of the extracellular fluid, and the concentration of Na⁺ inside the cell less than that of the extracellular fluid. The concentration differences established by this active transporter mean that K⁺ would diffuse out of the cell and Na⁺ would diffuse in if the ions could cross the lipid bilayer. How do these concentration gradients relate to the electrical gradients we discussed above?

Ion channels permit the diffusion of ions across membranes. These channels are water-filled pores formed by proteins that span the lipid bilayer and are generally selective, allowing some types of ions to pass through more easily than others (see Figure 6.11). Thus there are potassium channels, sodium channels, chloride channels, and calcium channels, and there are different kinds of channels for each ion. Ions can diffuse through these channels in either direction. The direction and magnitude of the net movement of ions through a channel depend on the concentration gradient of that ion type across the cell membrane, as well as on the voltage difference across that membrane. These two motive forces acting on an ion are termed its electrochemical gradient. Although the electrochemical gradient drives the movement of ions through channels, that movement is modified by gates that open and close the channels.

Potassium channels are the most common open, or leak, channels in the cell membranes of resting (nonstimulated) neurons. As a consequence, resting neurons are more permeable to K⁺ than to any other ion. Thus, open potassium channels are largely responsible for the resting membrane potential. Because the potassium channels make the cell membrane permeable to K⁺, and because the Na⁺–K⁺ pump keeps the concentration of K⁺ inside the cell much higher than that outside the cell, K⁺ tends to diffuse down its electrochemical gradient, out of the cell, through the channels. But, if K⁺ ions left the cell they would leave behind unbalanced negative charges, generating an electric potential across the membrane that tends to pull K⁺ back into the cell.

The membrane potential at which the net diffusion of K⁺ out of the cell ceases (that is, the point at which K⁺ diffusion out due to the concentration gradient is balanced by its inward movement due to the negative electric potential) is the potassium equilibrium potential, or E_K. The value of E_K can be calculated from the concentrations of K⁺ on the two sides of the membrane using the Nernst equation (Figure 44.5A). This equation, developed in the late 1800s, shows that the existence of ion channels in neuronal membranes was hypothesized long before their specific structures and properties were discovered.

In the late 1940s, A. L. Hodgkin and A. F. Huxley at the University of Cambridge set out to study the electrical properties of axonal membranes. With the techniques available at that time, the necessary measurements could be made only if you had a very large axon to work with. Such an axon exists in nature—the huge neuron that controls the escape response of squid. Hodgkin and Huxley used electrodes to measure the voltage across the cell membrane of this large axon, as seen in Figure 44.5, and to pass electric current into it to change its membrane potential. They also changed the concentrations of Na⁺ and K⁺ both inside and outside the squid axon and measured the resulting changes in membrane potential. On the basis of their many careful experiments, Hodgkin and Huxley developed virtually all of our basic concepts about the electrical properties of neurons, and they shared a Nobel Prize in 1963.

The resting potential of a neuron is less negative than the E_K calculated from the Nernst equation. This means that the resting potential is not due solely to leak K⁺ channels. The neuronal membrane is slightly permeable to other ions, especially Na⁺ and Cl^–, and movements of these ions influence the resting potential. A different equation takes into account (1) all of the ions that can cross the membrane and (2) the relative permeability of the membrane to those ions. This equation, called the Goldman equation, predicts the membrane potential more accurately than does the Nernst equation (Figure 44.5B).