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 (...pH), 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. (ProQuest: ... denotes formulae/symbols omitted.)
Voltage-gated proton channels are unique ion channels, membrane proteins that allow protons but no other ions to cross cell membranes. They are found in diverse species, from unicellular marine life ...to humans. In all cells, their function requires that they open and conduct current only under certain conditions, typically when the electrochemical gradient for protons is outwards. Consequently, these proteins behave like rectifiers, conducting protons out of cells. Their activity has electrical consequences and also changes the pH on both sides of the membrane. Here we summarize what is known about the way these proteins sense the membrane potential and the pH inside and outside the cell. Currently, it is hypothesized that membrane potential is sensed by permanently charged arginines (with very high pKa) within the protein, which results in parts of the protein moving to produce a conduction pathway. The mechanism of pH sensing appears to involve titratable side chains of particular amino acids. For this purpose their pKa needs to be within the operational pH range. We propose a ‘counter-charge’ model for pH sensing in which electrostatic interactions within the protein are selectively disrupted by protonation of internally or externally accessible groups.
A handful of biological proton-selective ion channels exist. Some open at positive or negative membrane potentials, others open at low or high pH, and some are light activated. This review focuses on ...common features that result from the unique properties of protons. Proton conduction through water or proteins differs qualitatively from that of all other ions. Extraordinary proton selectivity is needed to ensure that protons permeate and other ions do not. Proton selectivity arises from a proton pathway comprising a hydrogen-bonded chain that typically includes at least one titratable amino acid side chain. The enormously diverse functions of proton channels in disparate regions of the phylogenetic tree can be summarized by considering the chemical and electrical consequences of proton flux across membranes. This review discusses examples of cells in which proton efflux serves to increase pH
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, decrease pH
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, control the membrane potential, generate action potentials, or compensate transmembrane movement of electrical charge.
Summary
One of the most fascinating and exciting periods in my scientific career entailed dissecting the symbiotic relationship between two membrane transporters, the Nicotinamide adenine ...dinucleotide phosphate reduced form (NADPH) oxidase complex and voltage‐gated proton channels (HV1). By the time I entered this field, there had already been substantial progress toward understanding NADPH oxidase, but HV1 were known only to a tiny handful of cognoscenti around the world. Having identified the first proton currents in mammalian cells in 1991, I needed to find a clear function for these molecules if the work was to become fundable. The then‐recent discoveries of Henderson, Chappell, and colleagues in 1987–1988 that led them to hypothesize interactions of both molecules during the respiratory burst of phagocytes provided an excellent opportunity. In a nutshell, both transporters function by moving electrical charge across the membrane: NADPH oxidase moves electrons and HV1 moves protons. The consequences of electrogenic NADPH oxidase activity on both membrane potential and pH strongly self‐limit this enzyme. Fortunately, both consequences specifically activate HV1, and HV1 activity counteracts both consequences, a kind of yin–yang relationship. Notwithstanding a decade starting in 1995 when many believed the opposite, these are two separate molecules that function independently despite their being functionally interdependent in phagocytes. The relationship between NADPH oxidase and HV1 has become a paradigm that somewhat surprisingly has now extended well beyond the phagocyte NADPH oxidase – an industrial strength producer of reactive oxygen species (ROS) – to myriad other cells that produce orders of magnitude less ROS for signaling purposes. These cells with their seven NADPH oxidase (NOX) isoforms provide a vast realm of mechanistic obscurity that will occupy future studies for years to come.
The main properties of the voltage-gated proton channel (HV1) are described in this review, along with what is known about how the channel protein structure accomplishes its functions. Just as ...protons are unique among ions, proton channels are unique among ion channels. Their four transmembrane helices sense voltage and the pH gradient and conduct protons exclusively. Selectivity is achieved by the unique ability of H3O+ to protonate an Asp–Arg salt bridge. Pathognomonic sensitivity of gating to the pH gradient ensures HV1 channel opening only when acid extrusion will result, which is crucial to most of its biological functions. An exception occurs in dinoflagellates in which influx of H+ through HV1 triggers the bioluminescent flash. Pharmacological interventions that promise to ameliorate cancer, asthma, brain damage in ischemic stroke, Alzheimer’s disease, autoimmune diseases, and numerous other conditions await future progress.
Department of Molecular Biophysics and Physiology, Rush
Presbyterian St. Luke's Medical Center, Chicago,
Illinois
Decoursey, Thomas E.
Voltage-Gated Proton Channels and Other Proton Transfer
...Pathways. Physiol. Rev. 83: 475-579, 2003. 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.
The voltage-gated proton channel (HV1) is a unique molecule that resides at the interface between ion channels and bioenergetic molecules that use proton gradients to store or transduce energy. HV1 ...plays key roles in the health and disease of diverse tissues and species. Important information regarding the physical components of ion-channel gating (opening and closing, which in turn activate or terminate flow of ionic current through the pore) can be obtained by measuring the size, kinetics, and voltage dependence of gating currents. Measurement of gating currents in HV1 did not occur until a decade after the gene was identified. Gating currents are measured in other voltage-gated ion channels by first eliminating ionic currents either by blocking the current or by eliminating the permeant ion. Gating currents reflect the repositioning of a small number of charges within the protein each time the channel opens or closes, and thus would be dwarfed by the much larger ionic currents that flow at a high rate as long as the channel is open.
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