The relative difference in electrical charge, or voltage, between the inside and the outside of a cell membrane, is called the membrane potential. It is generated by differences in permeability of the membrane to various ions and the concentrations of these ions across the membrane.

The Inside of a Neuron is More Negative

The membrane potential of a cell can be measured by inserting a microelectrode into a cell and comparing the charge to a reference electrode in the extracellular fluid. The membrane potential of a neuron at rest—that is, a neuron not currently receiving or sending messages—is negative, typically around -70 millivolts (mV). This is called the resting membrane potential. The negative value indicates that the inside of the membrane is relatively more negative than the outside—it is polarized. The resting potential results from two major factors: selective permeability of the membrane and differences in ion concentration inside the cell compared to outside.

Membrane Permeability

Cell membranes are selectively permeable because most ions and molecules cannot cross the lipid bilayer without help, often from ion channel proteins that span the membrane. This is because the charged ions cannot diffuse through the uncharged hydrophobic interior of membranes. The most common intra- and extracellular ions found in the nervous tissue are potassium (K⁺), sodium (Na⁺), chloride (Cl^-), and calcium (Ca²⁺). When a neuron is at rest, potassium (K⁺) channels are the main type of ion channel that is open—allowing K⁺ to migrate across the membrane. This permeability, together with the large intracellular concentrations, make the neuron’s resting membrane potential determined mainly by the movement of K⁺.

Pumps Create Concentration Gradients

Differences in ion concentration between the inside and outside of neurons are primarily due to the activity of the sodium-potassium (Na⁺/K⁺) pump—a transmembrane protein that continuously pumps three Na+ ions out of the cell for every two K⁺ ions it pumps in. This establishes concentration gradients, with a higher concentration of Na⁺ ions outside of neurons and a higher concentration of K⁺ ions inside.

Since the membrane is primarily permeable to K⁺ at rest—due to the open K⁺ channels—K⁺ can diffuse down its concentration gradient to the region of lower concentration out of the cell. These positive charges leaving the cell, combined with the fact that there are many negatively charged proteins inside the cell, cause the inside to be relatively more negative.

Eventually, outward diffusion of K⁺ is balanced by the electrostatic repulsion of positive charges accumulating outside the cell, and electrochemical equilibrium is reached. The net effect is the observed negative resting potential. The resting potential is very important in the nervous system because changes in membrane potential—such as the action potential—are the basis for neural signaling.

Beware the Pufferfish

Pufferfish is not often found on many seafood menus outside of Japan, in part because they contain a potent neurotoxin. Tetrodotoxin (TTX) is a very selective voltage-gated sodium channel blocker that is lethal in minimal doses. The median lethal dose (LD50) for mice is 334 μg/kg, compared to 8.5 mg/kg for potassium cyanide. It has also served as an essential tool in neuroscience research. The toxin blocks the flow of Na⁺ into the cell when the channel opens. It, therefore, disrupts action potentials—but not the resting membrane potential—and can be used to silence neuronal activity. Its mechanism of action was demonstrated by Toshio Narahashi and John W. Moore at Duke University, working on the giant lobster axon in 1964.