Voltage-Gated Proton Channels: Molecular Biology, Physiology, and Pathophysiology of the HVFamily

Abstract

Voltage-gated proton channels (HV) are unique, in part because the ion they conduct is unique. HVchannels 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 HVchannel 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, HVchannels exist as dimers in which each protomer has its own conduction pathway, yet gating is cooperative. HVchannels are phylogenetically diverse, distributed from humans to unicellular marine life, and perhaps even plants. Correspondingly, HVfunctions 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 hHV1 may exacerbate breast cancer metastasis and cerebral damage from ischemic stroke highlights the rapidly expanding recognition of the clinical importance of hHV1.