Ion channel

Not to be confused with: Ion Television or Ion implantation.
Schematic diagram of an ion channel. 1 - channel domains (typically four per channel), 2 - outer vestibule, 3 - selectivity filter, 4 - diameter of selectivity filter, 5 - phosphorylation site, 6 - cell membrane.

Ion channels are pore-forming membrane proteins whose 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 considered to be one of the two traditional classes of ionophoric proteins, with the other class known as ion transporters (including the sodium-potassium pump, sodium-calcium exchanger, and sodium-glucose transport proteins, amongst others).[1]

Study of ion channels (channelomics) often includes biophysics, electrophysiology and pharmacology, utilizing techniques including voltage clamp, patch clamp, immunohistochemistry, X-ray crystallography, fluorescence, and RT-PCR.

Basic features

There are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins:[2]

  1. The rate of ion transport through the channel is very high (often 106 ions per second or greater).
  2. Ions pass through channels down their electrochemical gradient, which is a function of ion concentration and membrane potential, "downhill", without the input (or help) of metabolic energy (e.g. ATP, co-transport mechanisms, or active transport mechanisms).

Ion channels are located within the plasma membrane of nearly all cells and many intracellular organelles. They are often described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through. This characteristic is called selective permeability. The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as sodium or potassium. However, some channels may be permeable to the passage of more than one type of ion, typically sharing a common charge: positive (cations) or negative (anions). Ions often move through the segments of the channel pore in single file nearly as quickly as the ions move through free solution. In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force.

Ion channels are integral membrane proteins, typically formed as assemblies of several individual proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer.[3][4] For most voltage-gated ion channels, the pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on.

Biological role

Because channels underlie the nerve impulse and because "transmitter-activated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, numerous toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails, and others) work by modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a frequent target.[5][6][7]


There are over 300 types of ion channels in a living cell.[8] Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, the number of gates (pores) and localization of proteins.

Further heterogeneity of ion channels arises when channels with different constitutive subunits give rise to a specific kind of current.[9] Absence or mutation of one or more of the contributing types of channel subunits can result in loss of function and, potentially, underlie neurologic diseases.

Classification by gating

Ion channels may be classified by gating, i.e. what opens and closes the channels. Voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel.


Voltage-gated ion channels open and close in response to membrane potential.


Also known as ionotropic receptors, this group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of such channels include the cation-permeable "nicotinic" Acetylcholine receptor, ionotropic glutamate-gated receptors, acid sensing ion channels (ASICs),[10] ATP-gated P2X receptors, and the anion-permeable γ-aminobutyric acid-gated GABAA receptor.

Ion channels activated by second messengers may also be categorized in this group, although ligands and second messengers are otherwise distinguished from each other.

Other gating

Other gating include activation/inactivation by, e.g., second messengers from the inside of the cell membrane, rather than from outside, as in the case for ligands. Ions may count to such second messengers, and then causes direct activation, rather than indirect, as in the case were the electric potential of ions cause activation/inactivation of voltage-gated ion channels.

Classification by type of ions

Classification by localization

Ion channels are also classified according to their localization. Plasma membrane contains around 2~ of total membrane components, whereas intracellular organelles contain 98% cellular membrane. The major intracellular compartments are endoplasmic reticulum, Golgi apparatus and mitochondria. On the basis of localization ion channels are classified as

Other classifications

There are other types of ion channel classifications that are based on less normal characteristics, e.g. multiple pores and transient potentials.

Almost all ion channels have one single pore. However, there are also those with two:

There are channels that are classified by the duration of the response to stimuli:

Detailed structure

Channels differ with respect to the ion they let pass (for example, Na+, K+, Cl), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure.[11] Channels belonging to the largest class, which includes the voltage-gated channels that underlie the nerve impulse, consists of four subunits with six transmembrane helices each. On activation, these helices move about and open the pore. Two of these six helices are separated by a loop that lines the pore and is the primary determinant of ion selectivity and conductance in this channel class and some others. The existence and mechanism for ion selectivity was first postulated in the 1960s by Clay Armstrong.[12] He suggested that the pore lining could efficiently replace the water molecules that normally shield potassium ions, but that sodium ions were too small to allow such shielding, and therefore could not pass through. This mechanism was finally confirmed when the structure of the channel was elucidated. The channel subunits of one such other class, for example, consist of just this "P" loop and two transmembrane helices. The determination of their molecular structure by Roderick MacKinnon using X-ray crystallography won a share of the 2003 Nobel Prize in Chemistry.

Because of their small size and the difficulty of crystallizing integral membrane proteins for X-ray analysis, it is only very recently that scientists have been able to directly examine what channels "look like." Particularly in cases where the crystallography required removing channels from their membranes with detergent, many researchers regard images that have been obtained as tentative. An example is the long-awaited crystal structure of a voltage-gated potassium channel, which was reported in May 2003.[13][14] One inevitable ambiguity about these structures relates to the strong evidence that channels change conformation as they operate (they open and close, for example), such that the structure in the crystal could represent any one of these operational states. Most of what researchers have deduced about channel operation so far they have established through electrophysiology, biochemistry, gene sequence comparison and mutagenesis.

Channels can have single (CLICs) to multiple transmembrane (K channels, P2X receptors, Na channels) domains which span plasma membrane to form pores. Pore can determine the selectivity of the channel. Gate can be formed either inside or outside the pore region.

Ion channel blockers

A variety of inorganic and organic molecules can modulate ion channel activity and conductance. Some commonly used blockers include:


There are a number of disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic and autoimmune disorders of ion channels and their modifiers are known as channelopathies. See Category:Channelopathies for a full list.


The fundamental properties of currents mediated by ion channels were analyzed by the British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize-winning research on the action potential, published in 1952. They built on the work of other physiologists, such as Cole and Baker's research into voltage-gated membrane pores from 1941.[16][17] The existence of ion channels was confirmed in the 1970s by Bernard Katz and Ricardo Miledi using noise analysis. It was then shown more directly with an electrical recording technique known as the "patch clamp", which led to a Nobel Prize to Erwin Neher and Bert Sakmann, the technique's inventors. Hundreds if not thousands of researchers continue to pursue a more detailed understanding of how these proteins work. In recent years the development of automated patch clamp devices helped to increase significantly the throughput in ion channel screening.

The Nobel Prize in Chemistry for 2003 was awarded to two American scientists: Roderick MacKinnon for his studies on the physico-chemical properties of ion channel structure and function, including x-ray crystallographic structure studies, and Peter Agre for his similar work on aquaporins.[18]


Birth of an Idea (2007) by Julian Voss-Andreae. The sculpture was commissioned by Roderick MacKinnon based on the molecule's atomic coordinates that were determined by MacKinnon's group in 2001.

Roderick MacKinnon commissioned Birth of an Idea, a 5-foot (1.5 m) tall sculpture based on the KcsA potassium channel.[19] The artwork contains a wire object representing the channel's interior with a blown glass object representing the main cavity of the channel structure.

See also


  1. Hille, Bertil (2001) [1984]. Ion Channels of Excitable Membranes (3rd ed.). Sunderland, Mass: Sinauer Associates, Inc. p. 5. ISBN 0-87893-321-2.
  2. Hille, Bertil (1984). Ionic Channels of Excitable Membranes.
  3. Purves, (2001). "Chapter 4: Channels and Transporters". In Dale Purves; George J. Augustine; David Fitzpatrick; Lawrence. C. Katz; Anthony-Samuel LaMantia; James O. McNamara; S. Mark Williams. Neuroscience (2nd ed.). Sinauer Associates Inc. ISBN 0-87893-741-2.
  4. Hille B, Catterall, WA (1999). "Chapter 6: Electrical Excitability and Ion Channels". In George J Siegel; Bernard W Agranoff; R. W Albers; Stephen K Fisher; Michael D Uhler. Basic neurochemistry: molecular, cellular, and medical aspects. Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X.
  5. Camerino DC, Tricarico D, Desaphy JF (April 2007). "Ion channel pharmacology". Neurotherapeutics. 4 (2): 184–98. doi:10.1016/j.nurt.2007.01.013. PMID 17395128.
  6. Verkman AS, Galietta LJ (February 2009). "Chloride channels as drug targets". Nat Rev Drug Discov. 8 (2): 153–71. doi:10.1038/nrd2780. PMC 3601949Freely accessible. PMID 19153558.
  7. Camerino DC, Desaphy JF, Tricarico D, Pierno S, Liantonio A (2008). "Therapeutic approaches to ion channel diseases". Adv. Genet. Advances in Genetics. 64: 81–145. doi:10.1016/S0065-2660(08)00804-3. ISBN 978-0-12-374621-4. PMID 19161833.
  8. Gabashvili IS, Sokolowski BH, Morton CC, Giersch AB (September 2007). "Ion Channel Gene Expression in the Inner Ear". J. Assoc. Res. Otolaryngol. 8 (3): 305–28. doi:10.1007/s10162-007-0082-y. PMC 2538437Freely accessible. PMID 17541769.
  9. Vicini S (April 1999). "New perspectives in the functional role of GABA(A) channel heterogeneity". Mol. Neurobiol. 19 (2): 97–110. doi:10.1007/BF02743656. PMID 10371465.
  10. Hanukoglu I (2016). "ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters". FEBS Journal. doi:10.1111/febs.13840. PMID 27580245.
  11. Lim, Carmay; Dudev, Todor (2016). "Chapter 10. Potassium Versus Sodium Selectivity in Monovalent Ion Channel Selectivity Filters". In Astrid, Sigel; Helmut, Sigel; Roland K.O., Sigel. The Alkali Metal Ions: Their Role in Life. Metal Ions in Life Sciences. 16. Springer. pp. 325–347. doi:10.1007/978-4-319-21756-7_9.
  12. Bezanilla F, Armstrong CM (November 1972). "Negative Conductance Caused by Entry of Sodium and Cesium Ions into the Potassium Channels of Squid Axons". J. Gen. Physiol. 60 (5): 588–608. doi:10.1085/jgp.60.5.588. PMC 2226091Freely accessible. PMID 4644327.
  13. Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R (May 2003). "X-ray structure of a voltage-dependent K+ channel". Nature. 423 (6935): 33–41. Bibcode:2003Natur.423...33J. doi:10.1038/nature01580. PMID 12721618.
  14. The detailed 3D structure of the magnesium channel from bacteria can be seen here .
  15. Molenaar, Remco J. (2011). "Ion Channels in Glioblastoma". ISRN Neurology. 2011: 1. doi:10.5402/2011/590249. PMC 3263536Freely accessible. PMID 22389824.
  16. Pethig R, Kell DB (1987). "The passive electrical properties of biological systems: their significance in physiology, biophysics and biotechnology" (PDF). Phys. Med. Biol. 32 (8): 933–970. Bibcode:1987PMB....32..933P. doi:10.1088/0031-9155/32/8/001. PMID 3306721. An expansive review of bioelectrical characteristics from 1987. ... the observation of an inductance (negative capacitance) by Cole and Baker (1941) during measurements of the AC electrical properties of squid axons led directly to the concept of voltage-gated membrane pores, as embodied in the celebrated Hodgkin-Huxley (1952) treatment (Cole 1972, Jack er a1 1975), as the crucial mechanism of neurotransmission.
  17. Cole KS, Baker RF (February 1941). "Longitudinal Impedance of the Squid Giant Axon". The Journal of General Physiology. The Rockefeller University Press. 24 (6): 771–88. doi:10.1085/jgp.24.6.771. PMC 2238007Freely accessible. PMID 19873252. Describes what happens when you stick a giant squid axon with electrodes and pass through an alternating current, and then notice that sometimes the voltage rises with time, and sometimes it decreases. The inductive reactance is a property of the axon and requires that it contain an inductive structure. The variation of the impedance with interpolar distance indicates that the inductance is in the membrane
  18. "The Nobel Prize in Chemistry 2003" (Press release). The Royal Swedish Academy of Science. 2003-10-08. Retrieved 2010-01-18.
  19. Ball, Philip (March 2008). "The crucible: Art inspired by science should be more than just a pretty picture". Chemistry World. 5 (3): 42–43. Retrieved 2009-01-12.

External links

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