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Voltage-gated ion channel

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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 transmembrane proteins that form ion channels that are activated by changes in electrical membrane potential near the channel. The electrical membrane potential, or the difference in electrical charge on either side of a cell membrane, causes electromotive forces to drive ions toward either side of the membrane. 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.[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]

Each of the four homologous domains that make up one subunit of an ion channel. The S4 voltage-sensing segments are shown as charged.

Structure

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 α-subunits arranged around a central pore.[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 principle 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.[5] 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][6]

Mechanism

Crystallographic structural studies of potassium channels have shown that, when a potential difference is introduced over the membrane, the associated electric field 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 sufficient to depolarize the cell membrane.

Voltage-gated sodium channels and 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.[7] 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 from the cytoplasmic surface 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 in the protein that opens the channel.[4] The exact mechanism by which this movement occurs is not currently agreed upon.[8] Movement of the voltage-sensor triggers a conformational change of the gate of the conducing 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 conserved sequence, interchangeable across a wide variety of cells and species. A similar voltage sensor paddle has also been found in a family of voltage sensitive phosphatases in various species.[9] Genetic engineering of the paddle region from a species of volcano-dwelling archaebacteria into rat brain potassium channels results in a fully functional ion channel, as long as the whole intact paddle is replaced.[10] 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.[11]

Although voltage-gated ion channels are typically activated by membrane depolarization, 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.[12] 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,[13] the S6 segment breaks into two segments allowing of passing of ions through the channel,[14] or the S6 channel serves as the gate itself.[15] 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.[16] 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.[17] Fast inactivation is directly linked to the activation caused by intramembrane movements of the S4 segments,[18] 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 sodium channels have been identified, their functions are generally conserved between species and different cell types.[18]

Calcium (Ca2+) channels

With sixteen different identified genes for human calcium channels, this type of channel differs in function between cell types. Ca2+ channels give rise to action potentials similar to Na+ channels in some neurons. In most cells, Ca2+ channels regulate a wide variety of biochemical processes due to their role in controlling intracellular Ca2+ concentrations.[14] Many Ca2+ channel families are outside of the VIC superfamily.

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 influence 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 from most Na+ and Ca2+ channels of the VIC superfamily in that they contain four separate polypeptide subunits, while most Na+ and Ca2+ channels contain four homologous domains within a single polypeptide chain..[8]

Chloride (Cl-) channels

Chloride channels are found in several channel families that in general are not included in the VIC superfamily.  However, one family of Cl- channels, the Ca-CLC family, is a member of the VIC superfamily.[1]

Examples include:

Nomenclature

Based on examination of proteins expressed in bacteria, a superfamily of structurally homologous membrane proteins has been termed the voltage-gated ion channel (VIC) superfamily, consisting of the following nine families of ion channels and transporters:[19][20]

See also

References

  1. ^ a b Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Voltage-Gated Ion Channels.
  2. ^ Catterall, William A. (2000-04-01). "From Ionic Currents to Molecular Mechanisms". Neuron. 26 (1): 13–25. doi:10.1016/S0896-6273(00)81133-2. ISSN 0896-6273. PMID 10798388.
  3. ^ a b c d e Bezanilla, Francisco (2005-03-01). "Voltage-gated ion channels". IEEE transactions on nanobioscience. 4 (1): 34–48. ISSN 1536-1241. PMID 15816170.
  4. ^ a b Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 21.3, Molecular Properties of Voltage-Gated Ion Channels.
  5. ^ a b "1.A.1 The Voltage-gated Ion Channel (VIC) Superfamily". TCDB. Retrieved 2016-04-08.
  6. ^ Gulbis, J. M.; Mann, S.; MacKinnon, R. (1999-06-25). "Structure of a voltage-dependent K+ channel beta subunit". Cell. 97 (7): 943–952. ISSN 0092-8674. PMID 10399921.
  7. ^ Voltage sensor in the voltage gated sodium and potassium channels | PharmaXChange.info
  8. ^ a b Sands, Zara; Grottesi, Alessandro; Sansom, Mark S. P. (2005-01-26). "Voltage-gated ion channels". Current Biology 15 (2): R44–R47.doi:10.1016/j.cub.2004.12.050. ISSN 0960-9822.PMID 15668152.
  9. ^ Murata, Y.; Iwasaki, H.; Sasaki, M.; Inaba, K.; Okamura, Y. (2005). "Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor". Nature. 435 (7046): 1239–1243. doi:10.1038/nature03650. PMID 15902207.
  10. ^ Alabi AA, Bahamonde MI, Jung HJ, Kim JI, Swartz KJ (November 2007). "Portability of paddle motif function and pharmacology in voltage sensors". Nature. 450 (7168): 370–5. doi:10.1038/nature06266. PMC 2709416. PMID 18004375.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Long SB, Tao X, Campbell EB, MacKinnon R (November 2007). "Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment". Nature. 450 (7168): 376–82. doi:10.1038/nature06265. PMID 18004376.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ G. Yellen, “The moving parts of voltage-gated ion channels,” Q. Rev. Biophys., vol. 31, pp. 239–295, 1998.
  13. ^ E. Perozo, M. Cortes, and L. G. Cuello, “Structural rearrangements underlying K -channel activation gating,” Science, vol. 285, pp. 73–78.
  14. ^ a b Y. Jiang, A. Lee, J. Chen, M. Cadene, B. T. Chait, and R. MacKinnon, “Crystal structure and mechanism of a calcium-gated potassium channel,” Nature, vol. 417, pp. 515–522.
  15. ^ S. M. Webster, D. Del Camino, J. P. Dekker, and G. Yellen, “Intracellular gate opening in Shaker K channels defined by high-affinity metal bridges,” Nature, vol. 428, pp. 864–868, 2004.
  16. ^ Armstrong, C.M. (1981). Sodium channels and gating currents. Rev. 61, 644–682.
  17. ^ Vassilev, P.M., Scheuer, T., and Catterall, W.A. (1989). Inhibition of inactivation of single sodium channels by a site-directed antibody. Proc. Natl. Acad. Sci. USA 86, 8147–8151.
  18. ^ a b Benitah, J.P., Chen, Z.H., Balser, J.R., Tomaselli, G.F., and Marban, E. (1999). Molecular dynamics of the sodium channel pore vary with gating: interactions between P-segment motions and inactivation. J. Neurosci. 19, 1577–1585.
  19. ^ Koishi, Ryuta; Xu, Haoxing; Ren, Dejian; Navarro, Betsy; Spiller, Benjamin W.; Shi, Qing; Clapham, David E. (2004-03-05). "A superfamily of voltage-gated sodium channels in bacteria". The Journal of Biological Chemistry. 279 (10): 9532–9538. doi:10.1074/jbc.M313100200. ISSN 0021-9258. PMID 14665618.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  20. ^ a b TC# 1.A.1 The Voltage-gated Ion Channel (VIC) Family (Superfamily)
  21. ^ TC# 1.A.2
  22. ^ TC# 1.A.3
  23. ^ TC# 1.A.4
  24. ^ TC# 1.A.5
  25. ^ TC# 1.A.10
  26. ^ TC# 1.A.17
  27. ^ TC# 2.A.36
  28. ^ TC# 2.A.38
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