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

Abstract

Voltage-gated proton channels (HV) are unique, in part because the ion they conduct is unique. HV channels 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 HV channel 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, HV channels exist as dimers in which each protomer has its own conduction pathway, yet gating is cooperative. HV channels are phylogenetically diverse, distributed from humans to unicellular marine life, and perhaps even plants. Correspondingly, HV functions 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.

Resting state of the human proton channel dimer in a lipid bilayer

“…We have carried out this exercise independent of the recently reported X-ray structure of the mHv1/CiVSD/GNC4 chimera. Due to the common overall architecture of VSDs, structural models for hHv1 have been constructed based on existing structures from either KvAP or Kv1.2 VSDs (3,6,20,24). We point out that given local sequence similarity, the recently determined VSD from Ci-VSP (CiVSD) represents a more logical and accurate structural template for hHv1 (16).…”

Effect of electromagnetic waves on human reproduction

“…The voltage-gated channel Hv1, which is the sensor of electric voltage responsible for the alkalization of the intracellular environment necessary in the process of capacitation, hyperactivation, acrosomal response and sperm motility, seems to be most vulnerable to electromagnetic waves [15,16]. Based on the results of studies concerning the effect of electromagnetic waves on cells of the immune system, it is known that the effect of EMR modifies the transport of Ca ions to the cell, and the wave frequency close to 15 Hz exerts the strongest effect on this phenomenon [17].…”

Flagellar ion channels of sperm: similarities and differences between species

“…The first electrophysiological recording of voltage-dependent proton current in snail neurons were reported by Thomas and Meech [120]. Later studies, primarily done by DeCoursey group [121][122][123], found similar currents in other cell types [124]. However, controversy in the field on whether proton channels were in fact molecular entities had been present since 1989 after studies from Byerly and Suen [125].…”