Voltage-Gated Proton Channels and Other Proton Transfer Pathways

Abstract

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.