Voltage-gated ion channel

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TCDB
1.A.1
OPM superfamily8
OPM protein2a79
Ions are depicted by the red circles. A gradient is represented by the different concentration of ions on either side of the membrane. The open conformation of the ion channel allows for the translocation of ions across the cell membrane, while the closed conformation does not.

Voltage-gated ion channels are a class of

calcium (Ca2+), and chloride (Cl−) ions have been identified.[1] The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.[2]

Structure

Further information: Cation channel superfamily
Conformation of the four homologous domains showing the formation of a central pore

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 gradients. 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.[3] 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.[4] The membrane-spanning segments, designated S1-S6, all take the form of alpha helices 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.[3] 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 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.[5]

Mechanism

current
sufficient to depolarize the cell membrane.

calcium channels are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning alpha helices. One of these helices, S4, is the voltage sensing helix.[6]
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.[3] 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.[4] 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.[7]

Movement of the voltage-sensor triggers a conformational change of the gate of the conducting pathway, controlling the flow of ions through the channel.[3]

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

archaebacteria into rat brain potassium channels results in a fully functional ion channel, as long as the whole intact paddle is replaced.[9] This "modularity" 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.[10]

Although voltage-gated ion channels are typically activated by membrane

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.[11] 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,[12] the S6 segment breaks into two segments allowing of passing of ions through the channel,[13] or the S6 channel serving as the gate itself.[14] 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.[3]

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.[15] 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.[16] Fast inactivation is directly linked to the activation caused by intramembrane movements of the S4 segments,[17] though the mechanism linking movement of S4 and the engagement of the inactivation gate is unknown.

Different types

Sodium (Na+) channels

Sodium channels 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.[17]

Calcium (Ca2+) channels

Main article: Voltage-gated calcium channel
See also: Calcium channel blocker

With sixteen different identified genes for human calcium channels, this type of channel differs in function between cell types. Ca2+ channels produce action potentials similarly to Na+ channels in some neurons. They also play a role in neurotransmitter release 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.[13]

Potassium (K+) channels

Potassium channels 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.[7]

Chloride (Cl−) channels

Chloride channels 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.[1]

Proton (H+) channels

Voltage-gated proton channels carry currents mediated by hydrogen ions in the form of hydronium, and are activated by depolarization in a pH-dependent manner. They function to remove acid from cells.[18][19][20]

Phylogenetics

Further information:
Ion channel family

Phylogenetic studies of proteins expressed in bacteria revealed the existence of a superfamily of voltage-gated sodium channels.[21] Subsequent studies have shown that a variety of other ion channels and transporters are phylogenetically related to the voltage-gated ion channels, including:

See also

References

  1. ^
    ISBN 978-0-87893-742-4
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  2. PMID 10798388
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  3. ^
    S2CID 8212388
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  4. ^
    ISBN 978-0-7167-3136-8
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  5. PMID 10399921
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  6. PMID 20869590
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  7. ^
    PMID 15668152
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  8. S2CID 4427755
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  9. PMID 18004375
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  10. S2CID 4320272
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  11. S2CID 2605660
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  12. S2CID 26775433
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  13. ^
    S2CID 205029269
    .
  14. S2CID 1329210
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  15. PMID 6265962
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  16. PMID 2554301
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  17. ^
    PMID 10024345
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  18. PMID 7561747
  19. PMID 12663866
  20. PMID 20543828
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  21. PMID 14665618
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  22. S2CID 45284885
    .

External links
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