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Channel desensitization is entry into a less responsive or nonconducting state during sustained stimulation. A ligand-bound channel can therefore be closed without the ligand having dissociated.

Gating controls when an ion pathway is available; selectivity controls which ions can use it. An open ion channel permits passive movement down an electrochemical gradient. Opening does not itself specify current direction or guarantee a net current at the reversal potential. At a simple level, a population current can be written $I=N{P}_o\gamma (V-E_{\mathrm{rev}})$, separating channel number, open probability, single-channel conductance and driving force.

In a typical voltage-gated potassium channel, four subunits each contain six transmembrane helices. The S1–S4 region forms a voltage-sensing domain; S4 carries regularly spaced positive charges. A change in membrane potential alters the relative free energies of voltage-sensor conformations. Sensor rearrangement is coupled to opening of the S5–S6 pore region, including its intracellular activation gate. The charges do not have to traverse the entire membrane as free ions: protein conformational changes redistribute them through the electric field. A simple two-state approximation giveswhere $z_g$ is an effective gating charge and the sign convention makes depolarization favour opening for $z_g>0$. Real channels usually have multiple closed states and more complex kinetics.

voltage-gated sodium channels have four homologous domains in one polypeptide, with related voltage sensors and a central pore. Activation is followed by inactivation, which is a distinct process from the activation gate closing when the membrane repolarizes. Calcium channels share a related architecture. Voltage clamp can separate activation and inactivation kinetics, while gating-current measurements and voltage-sensor mutations test coupling between charge movement and pore opening. A mutation that abolishes current must be checked for expression and membrane delivery before concluding that it identifies the gate.

For potassium selectivity, the narrow selectivity filter contains backbone carbonyl oxygens arranged to coordinate largely dehydrated potassium ions. Binding and permeation balance the energetic cost of shedding water against favourable coordination within the filter. Sodium is smaller, but does not receive the same stabilization in the potassium-selective environment, so selectivity is not explained by a rigid hole that rejects all larger ions and admits all smaller ones. The KcsA structure established a concrete molecular basis for this principle.^[ref] KcsA itself is not the canonical S4 voltage-gated channel: its pore illustrates a conserved selectivity mechanism, not the voltage sensor just described. Voltage-gated sodium channels use a different filter chemistry; eukaryotic calcium-channel filters favour divalent calcium through an acidic coordination environment.

A ligand-gated ion channel instead couples ligand occupancy to changes in pore-opening probability. The nicotinic acetylcholine receptor is a pentamer with extracellular ligand-binding interfaces and a pore lined by M2 helices. Acetylcholine binding favours an opening-associated conformational change transmitted through the extracellular-to-transmembrane interface. Its pore conducts cations, including sodium and potassium, rather than selectively conducting only the transmitter or only sodium. Negatively charged regions and pore geometry favour cation over anion permeation. The ligand-binding site and the ion-selective pathway are spatially distinct, so the chemical identity of the bound transmitter does not define the permeant ion.

Rapid agonist exposure followed by freezing of Torpedo receptor membranes captured an opening-associated conformation, experimentally connecting ligand application to a receptor structural state.^[ref]

Other ligand-gated channels illustrate the independence of these properties: GABA-A receptors primarily support anion conductance, while glutamate-receptor channels support cation conductance with subtype-dependent calcium permeability. A sustained agonist can produce channel desensitization, in which an occupied receptor becomes nonconducting; occupancy is therefore not a permanently open instruction. Intracellular ligands can gate other channels, including ATP-dependent regulation, so “ligand-gated” need not imply an extracellular neurotransmitter.

The decisive tests separate binding, gating and permeation. Patch clamp resolves individual opening and closing events; rapid ligand application measures activation and desensitization; ion substitution and reversal-potential measurements constrain relative permeability. Changing a filter residue while retaining agonist binding and surface expression can implicate selectivity, while changing binding-site affinity without changing unitary conductance suggests a different role. Appropriate controls include leakage currents, solution junction potentials, channel abundance and ionic activities. A structure supplies candidate mechanisms; state-dependent electrophysiology establishes what those mechanisms do.