Voltage-gated Ion Channels
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Voltage-gated ion channels are a class of
transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
s that form
ion channel 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 io ...
s that are activated by changes in the electrical
membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing.
Cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s are generally impermeable to
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
al and muscle tissues, allowing a rapid and co-ordinated
depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
in response to triggering voltage change. Found along the
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
and at the
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to
sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
(Na+),
potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...
(K+),
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
(Ca2+), and
chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
(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.


Structure

Voltage-gated ion channels are generally composed of several subunits arranged in such a way that there is a central pore through which ions can travel down their
electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and th ...
s. The channels tend to be ion-specific, although similarly sized and charged ions may sometimes travel through them. The functionality of voltage-gated ion channels is attributed to its three main discrete units: the voltage sensor, the pore or conducting pathway, and the gate. Na+, K+, and Ca2+ channels are composed of four transmembrane domains arranged around a central pore; these four domains are part of a single α-subunit in the case of most Na+ and Ca2+ channels, whereas there are four α-subunits, each contributing one transmembrane domain, in most K+ channels. The membrane-spanning segments, designated S1-S6, all take the form of
alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
with specialized functions. The fifth and sixth transmembrane segments (S5 and S6) and pore loop serve the principal role of ion conduction, comprising the gate and pore of the channel, while S1-S4 serve as the voltage-sensing region. The four subunits may be identical, or different from one another. In addition to the four central α-subunits, there are also regulatory β-subunits, with
oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
activity, which are located on the inner surface of the cell membrane and do not cross the membrane, and which are coassembled with the α-subunits in the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
.


Mechanism

Crystallographic Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics (condensed matter physics). The word ...
structural studies of a
potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
have shown that, when a
potential difference Voltage, also known as electric pressure, electric tension, or (electric) potential difference, is the difference in electric potential between two points. In a static electric field, it corresponds to the work needed per unit of charge to m ...
is introduced over the membrane, the associated
electric field An electric field (sometimes E-field) is the physical field that surrounds electrically charged particles and exerts force on all other charged particles in the field, either attracting or repelling them. It also refers to the physical field fo ...
induces a conformational change in the potassium channel. The conformational change distorts the shape of the channel proteins sufficiently such that the cavity, or channel, opens to allow influx or efflux to occur across the membrane. This movement of ions down their concentration gradients subsequently generates an electric
current Currents, Current or The Current may refer to: Science and technology * Current (fluid), the flow of a liquid or a gas ** Air current, a flow of air ** Ocean current, a current in the ocean *** Rip current, a kind of water current ** Current (stre ...
sufficient to depolarize the cell membrane.
Voltage-gated sodium channels 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 and can be classified according to the trigger that opens the channel ...
and
calcium channels A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables ex ...
are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning
alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
. One of these helices, S4, is the voltage sensing helix. The S4 segment contains many positive charges such that a high positive charge outside the cell repels the helix, keeping the channel in its closed state. In general, the voltage sensing portion of the ion channel is responsible for the detection of changes in transmembrane potential that trigger the opening or closing of the channel. The S1-4 alpha helices are generally thought to serve this role. In potassium and sodium channels, voltage-sensing S4 helices contain positively-charged lysine or arginine residues in repeated motifs. In its resting state, half of each S4 helix is in contact with the cell cytosol. Upon depolarization, the positively-charged residues on the S4 domains move toward the exoplasmic surface of the membrane. It is thought that the first 4 arginines account for the gating current, moving toward the extracellular solvent upon channel activation in response to membrane depolarization. The movement of 10–12 of these protein-bound positive charges triggers a conformational change that opens the channel. The exact mechanism by which this movement occurs is not currently agreed upon, however the canonical, transporter, paddle, and twisted models are examples of current theories. Movement of the voltage-sensor triggers a conformational change of the gate of the conducting pathway, controlling the flow of ions through the channel. The main functional part of the voltage-sensitive protein domain of these channels generally contains a region composed of S3b and S4 helices, known as the "paddle" due to its shape, which appears to be a
conserved sequence In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor taxa ...
, interchangeable across a wide variety of cells and species. A similar voltage sensor paddle has also been found in a family of
voltage sensitive phosphatase Voltage sensitive phosphatases or voltage sensor-containing phosphatases, commonly abbreviated VSPs, are a protein family found in many species, including humans, mice, zebrafish, frogs, and sea squirt. Discovery The first voltage sensitive pho ...
s in various species.
Genetic engineering Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...
of the paddle region from a species of volcano-dwelling
archaebacteria Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebact ...
into rat brain potassium channels results in a fully functional ion channel, as long as the whole intact paddle is replaced. This "
modular Broadly speaking, modularity is the degree to which a system's components may be separated and recombined, often with the benefit of flexibility and variety in use. The concept of modularity is used primarily to reduce complexity by breaking a s ...
ity" allows use of simple and inexpensive model systems to study the function of this region, its role in disease, and pharmaceutical control of its behavior rather than being limited to poorly characterized, expensive, and/or difficult to study preparations. Although voltage-gated ion channels are typically activated by membrane
depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
, some channels, such as inward-rectifier potassium ion channels, are activated instead by hyperpolarization. The gate is thought to be coupled to the voltage sensing regions of the channels and appears to contain a mechanical obstruction to ion flow. While the S6 domain has been agreed upon as the segment acting as this obstruction, its exact mechanism is unknown. Possible explanations include: the S6 segment makes a scissor-like movement allowing ions to flow through, the S6 segment breaks into two segments allowing of passing of ions through the channel, or the S6 channel serving as the gate itself. The mechanism by which the movement of the S4 segment affects that of S6 is still unknown, however it is theorized that there is a S4-S5 linker whose movement allows the opening of S6. Inactivation of ion channels occurs within milliseconds after opening. Inactivation is thought to be mediated by an intracellular gate that controls the opening of the pore on the inside of the cell. This gate is modeled as a ball tethered to a flexible chain. During inactivation, the chain folds in on itself and the ball blocks the flow of ions through the channel. Fast inactivation is directly linked to the activation caused by intramembrane movements of the S4 segments, though the mechanism linking movement of S4 and the engagement of the inactivation gate is unknown.


Different types


Sodium (Na+) channels

Sodium channel 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 and can be classified according to the trigger that opens the channel ...
s have similar functional properties across many different cell types. While ten human genes encoding for sodium channels have been identified, their function is typically conserved between species and different cell types.


Calcium (Ca2+) channels

With sixteen different identified genes for human calcium channels, this type of channel differs in function between cell types. Ca2+ channels produce
action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
s similarly to Na+ channels in some neurons. They also play a role in
neurotransmitter release Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use ...
in pre-synaptic nerve endings. In most cells, Ca2+ channels regulate a wide variety of biochemical processes due to their role in controlling intracellular Ca2+ concentrations.


Potassium (K+) channels

Potassium channels Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
are the largest and most diverse class of voltage-gated channels, with over 100 encoding human genes. These types of channels differ significantly in their gating properties; some inactivating extremely slowly and others inactivating extremely quickly. This difference in activation time influences the duration and rate of action potential firing, which has a significant effect on electrical conduction along an axon as well as synaptic transmission. Potassium channels differ in structure from the other channels in that they contain four separate polypeptide subunits, while the other channels contain four homologous domain but on a single polypeptide unit.


Chloride (Cl) channels

Chloride channel Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Severa ...
s are present in all types of neurons. With the chief responsibility of controlling excitability, chloride channels contribute to the maintenance of cell resting potential and help to regulate cell volume.


Proton (H+) channels

Voltage-gated proton channel Voltage-gated proton channels are ion channels that have the unique property of opening with depolarization, but in a strongly pH-sensitive manner. The result is that these channels open only when the electrochemical gradient is outward, such tha ...
s carry currents mediated by
hydrogen ion A hydrogen ion is created when a hydrogen atom loses or gains an electron. A positively charged hydrogen ion (or proton) can readily combine with other particles and therefore is only seen isolated when it is in a gaseous state or a nearly particle ...
s in the form of
hydronium In chemistry, hydronium (hydroxonium in traditional British English) is the common name for the aqueous cation , the type of oxonium ion produced by protonation of water. It is often viewed as the positive ion present when an Arrhenius acid is d ...
, and are activated by depolarization in a pH-dependent manner. They function to remove acid from cells.


Phylogenetics

Phylogenetic In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...
studies of proteins expressed in bacteria revealed the existence of a
superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
of voltage-gated sodium channels. Subsequent studies have shown that a variety of other ion channels and transporters are phylogenetically related to the voltage-gated ion channels, including inwardly rectifying K+ channels, ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channels, transient receptor potential Ca2+ channels, polycystin cation channels, glutamate-gated ion channels, calcium-dependent chloride channels, monovalent cation:proton antiporters, type 1, and potassium transporters.


See also

*
Potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
*
Catecholaminergic polymorphic ventricular tachycardia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur du ...


References


External links


IUPHAR-DB Voltage-gated ion channel subunitsThe IUPHAR Compendium of Voltage-gated Ion Channels 2005
* {{Ion channels, g9 Ion channels Electrophysiology Integral membrane proteins