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Ion channel

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Pore-forming membrane protein that conducts ions and is opened and closed by gates

An ion channel is a protein that forms a pore through a cell membrane and lets certain ions cross it, in the direction their electric and concentration gradients push them. Roderick MacKinnon, in his Nobel lecture, gave the three properties that define one: channels conduct ions rapidly, many of them are highly selective, and their conduction is turned on and off by gating in response to a stimulus.[1] A survey of the human genome in 2009 counted at least 232 genes for the pore-forming subunits of ion channels in the plasma membrane.[2] Channels generate the nerve impulse, time the heartbeat, trigger the contraction of muscle and the secretion of insulin, and are the targets of many drugs and toxins.

A channel is a nanopore that evolved: a hole in a membrane, with a narrow constriction of molecular size, through which a current can be recorded. The current through one open channel is of the order of a picoampere. Nanopore sensing began as the recording of ion channels, and the amplifiers it uses were built for channels.

Properties

Conduction

At typical gradients in a cell a potassium channel passes between 107 and 108 ions per second, which MacKinnon noted approaches the rate at which potassium ions from solution collide with the entrance of the pore: the ions go through almost as fast as they arrive.[1] One picoampere is about 6.2 million singly charged ions per second, so those figures correspond to roughly 1.6 to 16 pA. A press piece on the company's live stream converted its current, 3.1 nA in the model value, to about 19 billion ions per second.[3] That is the flow through between 190 and 1,900 open potassium channels.

Selectivity

A potassium channel conducts potassium and nearly excludes sodium, although sodium ions are the smaller. A bacterial potassium channel from Streptomyces lividans, whose structure was solved to 3.2 Å in 1998, has four identical subunits that form an inverted cone around the pore. At its outer end the narrow selectivity filter, only 12 Å long, is lined by carbonyl oxygen atoms of the protein backbone and held open by structural constraints so that it fits potassium ions and not the smaller sodium ions. Two potassium ions sit in it about 7.5 Å apart, and the repulsion between them helps to push them through.[4] MacKinnon's account is that the oxygens stand in for the water that surrounds a potassium ion in solution, paying the energetic cost of removing it. Sodium is too small to fit the sites, so its cost is not repaid.[1]

Gating

Gating is slower than conduction and involves large changes in the shape of the protein. Channels are opened by voltage, by the binding of a molecule, by mechanical force or by temperature. In the KcsA channel, gating is controlled by acidity inside the cell and by the composition of the lipid membrane, and in laboratory assays its probability of being open reaches only a few percent.[1]

History

The Hodgkin-Huxley model of 1952 described the sodium and potassium conductances of a nerve membrane without saying what carried them. In 1955 Alan Hodgkin and Richard Keynes, measuring the flow of radioactive potassium across a nerve fiber, suggested that "the ions should be constrained to move in single file and that there should, on average, be several ions in a channel at any moment". Over the next two decades Clay Armstrong and Bertil Hille showed with electrical measurements that sodium and potassium cross the membrane through separate protein pores, and developed the ideas of a selectivity filter and a gate.[1]

Single channels were first heard in artificial membranes. In 1970 Stuart Hladky and Denis Haydon reported that the conductance of a lipid bilayer in the presence of certain antibiotics changed in discrete steps, each the opening or closing of one channel.[5] The patch clamp of Neher and Sakmann brought the same resolution to real cells in 1976 and earned them the 1991 Nobel Prize.[6][7]

Molecular biology reached channels in the 1980s. Cloned DNA gave the amino acid sequence of a subunit of the acetylcholine receptor of the electric ray Torpedo in 1982 and of the sodium channel of the electric eel in 1984.[8][9] The cloning of the Shaker gene of the fruit fly in 1987 and 1988, by the groups of Lily and Yuh Nung Jan, Mark Tanouye and Olaf Pongs, revealed the sequence of a potassium channel for the first time. MacKinnon then used charybdotoxin, a protein from scorpion venom that plugs the pore, to find which amino acids of Shaker line it, and went on to the structure of 1998.[1][4] He received half of the 2003 Nobel Prize in Chemistry "for structural and mechanistic studies of ion channels"; the other half went to Peter Agre for water channels.[10]

In 2021 David Julius and Ardem Patapoutian shared the Nobel Prize in Physiology or Medicine "for their discoveries of receptors for temperature and touch". Julius's group had identified the capsaicin receptor, the receptor for the pungent ingredient of chili peppers, as a heat-activated channel in 1997, and Patapoutian's group identified the mechanically activated channels Piezo1 and Piezo2 in 2010.[11][12][13]

Medicine

The Nobel Assembly said in 1991 that single-channel recording had helped to explain the mechanisms of diseases including diabetes and cystic fibrosis, and that drugs commonly used to stimulate insulin secretion act directly on ATP-controlled ion channels.[7] The safety guideline ICH S7B (2005) recommends an in vitro assay of the current through the potassium channel encoded by hERG, since blocking it is the most common way a drug delays the repolarization of the heart's ventricles.[14]

Channels as nanopores

In 1994 Sergey Bezrukov, Igor Vodyanoy and Adrian Parsegian used the channels formed by the peptide alamethicin to count single polymer molecules as they entered, in a paper that opened with a description of the Coulter counter.[15] Most channels are a poor choice for a sensor because they gate. Alpha-hemolysin, a toxin of Staphylococcus aureus, can stay open for long periods, and in 1996 it carried single strands of DNA and RNA through a membrane, each appearing as a dip in the ionic current.[16] See Biological nanopore and History of nanopore sequencing.

Molecular Reality Corporation builds solid-state nanopores and not protein pores. In the company's sliding-occlusion design the opening of the juxtapore is set by one membrane moving sideways over another.[17] A channel's gate is a protein that changes shape.

See also

References

  1. ^ a b c d e f MacKinnon, Roderick (2004). "Nobel lecture. Potassium channels and the atomic basis of selective ion conduction". Bioscience Reports 24 (2): 75-100. doi:10.1007/s10540-004-7190-2.
  2. ^ Nayak, Tapan K.; et al. (2009). "Evolution of the human ion channel set". Combinatorial Chemistry & High Throughput Screening 12 (1): 2-23. doi:10.2174/138620709787047957.
  3. ^ Lenora Ashgrove (July 29, 2026). "Nineteen Billion Ions a Second, Live on the Internet". Signal & Noise.
  4. ^ a b Doyle, D. A.; Cabral, J. M.; Pfuetzner, R. A.; Kuo, A.; Gulbis, J. M.; Cohen, S. L.; Chait, B. T.; MacKinnon, R. (1998). "The structure of the potassium channel: molecular basis of K+ conduction and selectivity". Science 280 (5360): 69-77. doi:10.1126/science.280.5360.69.
  5. ^ Hladky, S. B.; Haydon, D. A. (1970). "Discreteness of conductance change in bimolecular lipid membranes in the presence of certain antibiotics". Nature 225 (5231): 451-453. doi:10.1038/225451a0.
  6. ^ Neher, E.; Sakmann, B. (1976). "Single-channel currents recorded from membrane of denervated frog muscle fibres". Nature 260 (5554): 799-802. doi:10.1038/260799a0.
  7. ^ a b "The Nobel Prize in Physiology or Medicine 1991: Press release". Nobel Assembly at the Karolinska Institute. Retrieved October 25, 2026.
  8. ^ Noda, M.; Takahashi, H.; Tanabe, T.; et al. (1982). "Primary structure of α-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence". Nature 299 (5886): 793-797. doi:10.1038/299793a0.
  9. ^ Noda, M.; Shimizu, S.; Tanabe, T.; et al. (1984). "Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence". Nature 312 (5990): 121-127. doi:10.1038/312121a0.
  10. ^ "The Nobel Prize in Chemistry 2003: Press release". Royal Swedish Academy of Sciences. Retrieved October 25, 2026.
  11. ^ "The Nobel Prize in Physiology or Medicine 2021". NobelPrize.org. Retrieved October 25, 2026.
  12. ^ Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.; Julius, D. (1997). "The capsaicin receptor: a heat-activated ion channel in the pain pathway". Nature 389 (6653): 816-824. doi:10.1038/39807.
  13. ^ Coste, B.; Mathur, J.; Schmidt, M.; et al. (2010). "Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels". Science 330 (6000): 55-60. doi:10.1126/science.1193270.
  14. ^ "ICH S7B: Nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals". European Medicines Agency. 2005. Retrieved October 25, 2026.
  15. ^ Bezrukov, S. M.; Vodyanoy, I.; Parsegian, V. A. (1994). "Counting polymers moving through a single ion channel". Nature 370 (6487): 279-281. doi:10.1038/370279a0. PMID 7518571.
  16. ^ Kasianowicz, J. J.; Brandin, E.; Branton, D.; Deamer, D. W. (1996). "Characterization of individual polynucleotide molecules using a membrane channel". Proceedings of the National Academy of Sciences 93 (24): 13770-13773. doi:10.1073/pnas.93.24.13770.
  17. ^ "US10908144B2: Stacks of coaligned nanopores and fabrication and uses thereof". Google Patents. February 2, 2021. Retrieved October 25, 2026.
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