Voltage-gated proton channel

Last updated
Identifiers
SymbolHv
TCDB 1.A.51
OPM superfamily 8
OPM protein 3wkv

Voltage-gated proton channels are ion channels that have the unique property of opening with depolarization, but in a strongly pH-sensitive manner. [1] The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells. [2]

Another important function occurs in phagocytes (e.g. eosinophils, neutrophils, and macrophages) during the respiratory burst. When bacteria or other microbes are engulfed by phagocytes, the enzyme NADPH oxidase assembles in the membrane and begins to produce reactive oxygen species (ROS) that help kill bacteria. [3] NADPH oxidase is electrogenic, [4] moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically. [5] The functional expression of Hv1 in phagocytes has been well characterized in mammals, and recently in zebrafish, [6] suggesting its important roles in the immune cells of mammals and non-mammalian vertebrates. A group of small molecule inhibitors of the Hv1 channel are shown as chemotherapeutics and anti-inflammatory agents. [7]

When activated, the voltage-gated proton channel HV1 can allow up to 100,000 hydrogen ions across the membrane each second. [8] Whereas most voltage-gated ion channels contain a central pore that is surrounding by alpha helices and the voltage-sensing domain (VSD), voltage-gated hydrogen channels contain no central pore, [9] so their voltage-sensing regions (VSD) carry out the job of bringing acidic protons across the membrane. Because the relative H+ concentrations on each side of the membrane result in a pH gradient, these voltage-gated hydrogen channels only carry outward current, meaning they are used to move acidic protons out of the membrane. As a result, the opening of voltage-gated hydrogen channels usually hyperpolarize the cell membrane, or makes the membrane potential more negative. [10]

A recent discovery has shown that the voltage-gated proton channel Hv1 is highly expressed in human breast tumor tissues that are metastatic, but not in non-metastatic breast cancer tissues. [11] Because it has also been found to be highly expressed in other cancer tissues, [12] the study of the voltage-gated proton channel has led many scientists to wonder what its importance is in cancer metastasis. However, much is still being discovered concerning the structure and function of the voltage-gated proton channel.

Known types

Related Research Articles

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Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">BK channel</span> Family of transport proteins

BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

<span class="mw-page-title-main">Axon hillock</span> Part of the neuronal cell soma from which the axon originates

The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. It can be identified using light microscopy from its appearance and location in a neuron and from its sparse distribution of Nissl substance.

<span class="mw-page-title-main">Repolarization</span> Change in membrane potential

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

<span class="mw-page-title-main">NOX2</span> Protein-coding gene in the species Homo sapiens

NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene. The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

<span class="mw-page-title-main">Apocynin</span> Chemical compound

Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. It has been isolated from a variety of plant sources and is being studied for its variety of pharmacological properties.

<span class="mw-page-title-main">Cytochrome b-245, alpha polypeptide</span> Protein-coding gene in the species Homo sapiens

Cytochrome b-245 light chain is a protein that in humans is encoded by the CYBA gene involved in superoxide production and phagocytosis.

<span class="mw-page-title-main">Neutrophil cytosolic factor 4</span> Protein-coding gene in the species Homo sapiens

Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.

<span class="mw-page-title-main">KCNB1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

<span class="mw-page-title-main">VDAC1</span> Protein-coding gene in the species Homo sapiens

Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the VDAC1 gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membrane. In the OMM, it allows ATP to diffuse out of the mitochondria into the cytoplasm. In the cell membrane, it is involved in volume regulation. Within all eukaryotic cells, mitochondria are responsible for synthesis of ATP among other metabolite needed for cell survival. VDAC1 therefore allows for communication between the mitochondrion and the cell mediating the balance between cell metabolism and cell death. Besides metabolic permeation, VDAC1 also acts as a scaffold for proteins such as hexokinase that can in turn regulate metabolism.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

<span class="mw-page-title-main">Gating (electrophysiology)</span>

In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.

<span class="mw-page-title-main">HVCN1</span> Protein-coding gene in the species Homo sapiens

Voltage-gated hydrogen channel 1 is a protein that in humans is encoded by the HVCN1 gene.

References

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  6. Ratanayotha A, Kawai T, Higashijima SI, Okamura Y (August 2017). "Molecular and functional characterization of the voltage-gated proton channel in zebrafish neutrophils". Physiological Reports. 5 (15): e13345. doi:10.14814/phy2.13345. PMC   5555884 . PMID   28774948.
  7. Hong L, Pathak MM, Kim IH, Ta D, Tombola F (January 2013). "Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains". Neuron. 77 (2): 274–87. doi:10.1016/j.neuron.2012.11.013. PMC   3559007 . PMID   23352164.
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  9. DeCoursey TE, Morgan D, Musset B, Cherny VV (August 2016). "Insights into the structure and function of HV1 from a meta-analysis of mutation studies". The Journal of General Physiology. 148 (2): 97–118. doi:10.1085/jgp.201611619. PMC   4969798 . PMID   27481712.
  10. Shen Y, Luo Y, Liao P, Zuo Y, Jiang R (July 2023). "Role of the Voltage-Gated Proton Channel Hv1 in Nervous Systems". Neurosci Bull. 39 (7): 1157–1172. doi:10.1007/s12264-023-01053-6. PMC   10313628 . PMID   37029856.
  11. Wang Y, Li SJ, Pan J, Che Y, Yin J, Zhao Q (August 2011). "Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis". Biochemical and Biophysical Research Communications. 412 (2): 353–9. doi:10.1016/j.bbrc.2011.07.102. PMID   21821008.
  12. Wang Y, Wu X, Li Q, Zhang S, Li SJ (2013). "Human voltage-gated proton channel hv1: a new potential biomarker for diagnosis and prognosis of colorectal cancer". PLOS ONE. 8 (8): e70550. Bibcode:2013PLoSO...870550W. doi: 10.1371/journal.pone.0070550 . PMC   3734282 . PMID   23940591.