Proton channels exist in a wide variety of membrane proteins where they transport protons rapidly and efficiently. Usually the proton pathway is formed mainly by water molecules present in the protein, but its function is regulated by titratable groups on critical amino acid residues in the pathway. All proton channels conduct protons by a hydrogen-bonded chain mechanism in which the proton hops from one water or titratable group to the next. Voltage-gated proton channels represent a specific subset of proton channels that have voltage- and time-dependent gating like other ion channels. However, they differ from most ion channels in their extraordinarily high selectivity, tiny conductance, strong temperature and deuterium isotope effects on conductance and gating kinetics, and insensitivity to block by steric occlusion. Gating of H⁺channels is regulated tightly by pH and voltage, ensuring that they open only when the electrochemical gradient is outward. Thus they function to extrude acid from cells. H⁺channels are expressed in many cells. During the respiratory burst in phagocytes, H⁺current compensates for electron extrusion by NADPH oxidase. Most evidence indicates that the H⁺channel is not part of the NADPH oxidase complex, but rather is a distinct and as yet unidentified molecule.

Voltage-gated proton channels (H_V) are unique, in part because the ion they conduct is unique. H_Vchannels are perfectly selective for protons and have a very small unitary conductance, both arguably manifestations of the extremely low H⁺concentration in physiological solutions. They open with membrane depolarization, but their voltage dependence is strongly regulated by the pH gradient across the membrane (ΔpH), with the result that in most species they normally conduct only outward current. The H_Vchannel protein is strikingly similar to the voltage-sensing domain (VSD, the first four membrane-spanning segments) of voltage-gated K⁺and Na⁺channels. In higher species, H_Vchannels exist as dimers in which each protomer has its own conduction pathway, yet gating is cooperative. H_Vchannels are phylogenetically diverse, distributed from humans to unicellular marine life, and perhaps even plants. Correspondingly, H_Vfunctions vary widely as well, from promoting calcification in coccolithophores and triggering bioluminescent flashes in dinoflagellates to facilitating killing bacteria, airway pH regulation, basophil histamine release, sperm maturation, and B lymphocyte responses in humans. Recent evidence that hH_V1 may exacerbate breast cancer metastasis and cerebral damage from ischemic stroke highlights the rapidly expanding recognition of the clinical importance of hH_V1.