Ion channels maintain the membrane potential of a cell. For most cells, especially excitable ones, the inside has a more negative charge than the outside of the cell, due to a greater number of negative ions than positive ions. For excitable cells, like firing neurons, contracting muscle cells, or sensory touch cells, the membrane potential must be able to change rapidly moving from a negative membrane potential to one that is more positive. To achieve this, cells rely on two types of ion channels: ligand-gated and voltage-gated.

Ligand-gated ion channels, also called ionotropic receptors, are transmembrane proteins that form a channel but which also have a binding site. When a ligand binds to the surface, it opens the ion channel. Common ionotropic receptors include the NMDA, kainate, and AMPA glutamate receptors and the nicotinic acetylcholine receptors. While the majority of ionotropic receptors are activated by extracellular binding of neurotransmitters such as glutamate or acetylcholine, a few can be intracellularly activated by ions themselves.

When a ligand, like glutamate or acetylcholine, binds to its receptor it allows the influx of sodium (Na⁺) and calcium (Ca²⁺) ions into the cells. The positive ions, or cations, follow down their electrochemical gradient, moving from the more positive extracellular surface to the less positive (more negative) intracellular surface. This changes the membrane potential near the receptor, which can then activate nearby voltage gated ion channels to propagate the change in membrane potential throughout the cell.

Another ligand gated ion channel, the GABA_A receptor, permits chloride ion (Cl^-) into the cells. This actually lowers the membrane potential, limiting the propagating effects and inhibiting the excitable cell.

Voltage-gated ion channels open or close in response to changes in membrane potential, such as when a neighboring ligand-gated ion channel opens. There are several different types of voltage-gated channels that have selective permeability, meaning ions are filtered by size and charge. Voltage-gated calcium channels are important for muscle contraction and neurotransmitter release. Potassium channels work to repolarize the cell membrane after an action potential. Voltage-gated proton channels open during depolarization to remove protons from the cell.

Ion channels may play a role in migraine headaches. The dura mater is a protective covering for the brain. It is innervated by several cranial nerves. It is hypothesized that migraine originates in these nerves. Both ligand- and voltage-gated ion channels in the dura mater may potentiate pain signals by altering membrane potentials.