In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes. Furthermore potassium channels are found in most cell types and control a wide variety of cell functions.
Potassium channels function to conduct potassium ions down their electrochemical gradient, doing so both rapidly (up to the diffusion rate of K+ ions in bulk water) and selectively (excluding, most notably, sodium despite the sub-angstrom difference in ionic radius). Biologically, these channels act to set or reset the resting potential in many cells. In excitable cells, such as neurons, the delayed counterflow of potassium ions shapes the action potential.
By contributing to the regulation of the action potential duration in cardiac muscle, malfunction of potassium channels may cause life-threatening arrhythmias. Potassium channels may also be involved in maintaining vascular tone.
There are four major classes of potassium channels:
- Calcium-activated potassium channel - open in response to the presence of calcium ions or other signalling molecules.
- Inwardly rectifying potassium channel - passes current (positive charge) more easily in the inward direction (into the cell).
- Tandem pore domain potassium channel - are constitutively open or possess high basal activation, such as the "resting potassium channels" or "leak channels" that set the negative membrane potential of neurons.
- Voltage-gated potassium channel - are voltage-gated ion channels that open or close in response to changes in the transmembrane voltage.
The following table contains a comparison of the major classes of potassium channels with representative examples (for a complete list of channels within each class, see the respective class pages).
6T & 1P
2T & 1P
|Tandem pore domain
4T & 2P
6T & 1P
Potassium channels have a tetrameric structure in which four identical protein subunits associate to form a fourfold symmetric (C4) complex arranged around a central ion conducting pore (i.e., a homotetramer). Alternatively four related but not identical protein subunits may associate to form heterotetrameric complexes with pseudo C4 symmetry. All potassium channel subunits have a distinctive pore-loop structure that lines the top of the pore and is responsible for potassium selective permeability.
There are over 80 mammalian genes that encode potassium channel subunits. However potassium channels found in bacteria are amongst the most studied of ion channels, in terms of their molecular structure. Using X-ray crystallography, profound insights have been gained into how potassium ions pass through these channels and why (smaller) sodium ions do not. The 2003 Nobel Prize for Chemistry was awarded to Rod MacKinnon for his pioneering work in this area.
Potassium ion channels remove the hydration shell from the ion when it enters the selectivity filter. The selectivity filter is formed by a five residue sequence, TVGYG, termed the signature sequence, within the P loop of each subunit. This signature sequence is highly conserved, with the exception that an isoleucine residue in eukaryotic potassium ion channels often is substituted with a valine residue in prokaryotic channels. This sequence in the P-loop adopts a unique structure, having their electro-negative carbonyl oxygen atoms aligned toward the centre of the filter pore and form a square anti-prism similar to a water-solvating shell around each potassium binding site. The distance between the carbonyl oxygens and potassium ions in the binding sites of the selectivity filter is the same as between water oxygens in the first hydration shell and a potassium ion in water solution, providing an energetically favorable route for de-solvation of the ions. The selectivity filter opens towards the extracellular solution, exposing four carbonyl oxygens in a glycine residue (Gly79 in KcsA). The next residue toward the extracellular side of the protein is the negatively charged Asp80 (KcsA). This residue together with the five filter residues form the pore that connects the water-filled cavity in the centre of the protein with the extracellular solution.
The mechanism of potassium channel selectivity remains under continued debate. The carbonyl oxygens are strongly electro-negative and cation-attractive. The filter can accommodate potassium ions at 4 sites usually labelled S1 to S4 starting at the extracellular side. In addition, one ion can bind in the cavity at a site called SC or one or more ions at the extracellular side at more or less well-defined sites called S0 or Sext. Several different occupancies of these sites are possible. Since the X-ray structures are averages over many molecules, it is, however, not possible to deduce the actual occupancies directly from such a structure. In general, there is some disadvantage due to electrostatic repulsion to have two neighboring sites occupied by ions. Proposals for the mechanism of selectivity have been made based on molecular dynamics simulations, toy models of ion binding, thermodynamic calculations, topological considerations, and structural differences between selective and non-selective channels.
The mechanism for ion translocation in KcsA has been studied extensively by theoretical calculations and simulation. The prediction of an ion conduction mechanism in which the two doubly occupied states (S1, S3) and (S2, S4) play an essential role has been affirmed by both techniques. MD simulations suggest the two extracellular states, Sext and S0, reflecting ions entering and leaving the filter, also are important actors in ion conduction.
This region is used to neutralize the environment around the potassium ion so that it is not attracted to any charges. In turn, it speeds up the reaction.
A central pore, 10 Å wide, is located near the center of the transmembrane channel, where the energy barrier is highest for the transversing ion due to the hydrophobity of the channel wall. The water-filled cavity and the polar C-terminus of the pore helices ease the energetic barrier for the ion. Repulsion by preceding multiple potassium ions is thought to aid the throughput of the ions. The presence of the cavity can be understood intuitively as one of the channel's mechanisms for overcoming the dielectric barrier, or repulsion by the low-dielectric membrane, by keeping the K+ ion in a watery, high-dielectric environment.
The flux of ions through the potassium channel pore is regulated by two related processes, termed gating and inactivation. Gating is the opening or closing of the channel in response to stimuli, while inactivation is the rapid cessation of current from an open potassium channel and the suppression of the channel's ability to resume conducting. While both processes serve to regulate channel conductance, each process may be mediated by a number of mechanisms.
Generally, gating is though to be mediated by additional structural domains which sense stimuli and in turn open the channel pore. These domains include the RCK domains of BK channels, and voltage sensor domains of voltage gated K+ channels. These domains are thought to respond to the stimuli by physically opening the intracellular gate of the pore domain, thereby allowing potassium ions to traverse the membrane. Some channels have multiple regulatory domains or accessory proteins, which can act to modulate the response to stimulus. While the mechanisms continue to be debated, there are known structures of a number of these regulatory domains, including RCK domains of prokayrotic and eukaryotic channels, pH gating domain of KcsA, and voltage gated potassium channels.
N-type inactivation is typically the faster inactivation mechanism, and is termed the "ball and chain" model. N-type inactivation involves interaction of the N-terminus of the channel, or an associated protein, which interacts with the pore domain and occludes the ion conduction pathway like a "ball". Alternatively, C-type inactivation is though to occur within the selectivity filter itself, where structural changes within the filter render it non-conductive. There are a number of structural models of C-type inactivated K+ channel filters, although the precise mechanism remains unclear.
These blockers work in a way to inhibit the flow of potassium ions through the KcsA channel. They either compete with potassium when binding to KcsA channel or they bind to the outside of the channel on an external binding site causing a conformational change, which closes the channel. An example of one of these competitors is quaternary ammonium ions, thought to be toxins that inhibit the binding of potassium. In a study it was found that Tyr82 residues provides a good external binding site for blockers, especially the quaternary ammonium ions.
Muscarinic potassium channel
Some types of potassium channels are activated by muscarinic receptors and these are called muscarinic potassium channels (IKACh). These channels are a heterotetramer composed of two GIRK1 and two GIRK4 subunits. Examples are potassium channels in the heart, which, when activated by parasympathetic signals through M2 muscarinic receptors, cause an outward current of potassium, which slows down the heart rate.
Potassium channels in fine art
Roderick MacKinnon commissioned Birth of an Idea, a 5-foot (1.5 m) tall sculpture based on the KcsA potassium channel. The artwork contains a wire object representing the channel's interior with a blown glass object representing the main cavity of the channel structure.
- Littleton JT, Ganetzky B (2000). "Ion channels and synaptic organization: analysis of the Drosophila genome". Neuron 26 (1): 35–43. doi:10.1016/S0896-6273(00)81135-6. PMID 10798390.
- Hille, Bertil (2001). "Chapter 5: Potassium Channels and Chloride Channels". Ion channels of excitable membranes. Sunderland, Mass: Sinauer. pp. 131–168. ISBN 0-87893-321-2.
- Jessell, Thomas M., Kandel, Eric R., Schwartz, James H. (2000). "Chapter 6: Ion Channels". Principles of Neural Science (4th ed.). New York: McGraw-Hill. pp. 105–124. ISBN 0-8385-7701-6.
- Rang, HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 60. ISBN 0-443-07145-4.
- Kobayashi T, Washiyama K, Ikeda K (2006). "Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil". Neuropsychopharmacology 31 (3): 516–24. doi:10.1038/sj.npp.1300844. PMID 16123769.
- Enyedi P, Czirják G (2010). "Molecular background of leak K+ currents: two-pore domain potassium channels". Physiological Reviews 90 (2): 559–605. doi:10.1152/physrev.00029.2009. PMID 20393194.
- Lotshaw DP (2007). "Biophysical, pharmacological, and functional characteristics of cloned and native mammalian two-pore domain K+ channels". Cell Biochemistry and Biophysics 47 (2): 209–56. doi:10.1007/s12013-007-0007-8. PMID 17652773.
- Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, Lazdunski M (1998). "A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids". The EMBO Journal 17 (12): 3297–308. doi:10.1093/emboj/17.12.3297. PMC 1170668. PMID 9628867.
- Goldstein SA, Bockenhauer D, O'Kelly I, Zilberberg N (2001). "Potassium leak channels and the KCNK family of two-P-domain subunits". Nature Reviews Neuroscience 2 (3): 175–84. doi:10.1038/35058574. PMID 11256078.
- Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H, Matsushime H, Furuichi K (2003). "A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord". The Journal of Biological Chemistry 278 (30): 27406–12. doi:10.1074/jbc.M206810200. PMID 12754259.
- Czirják G, Tóth ZE, Enyedi P (2004). "The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin". The Journal of Biological Chemistry 279 (18): 18550–8. doi:10.1074/jbc.M312229200. PMID 14981085.
- Kindler CH, Yost CS, Gray AT (1999). "Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem". Anesthesiology 90 (4): 1092–102. doi:10.1097/00000542-199904000-00024. PMID 10201682.
- Meadows HJ, Randall AD (2001). "Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel". Neuropharmacology 40 (4): 551–9. doi:10.1016/S0028-3908(00)00189-1. PMID 11249964.
- Kindler CH, Paul M, Zou H, Liu C, Winegar BD, Gray AT, Yost CS (2003). "Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5)". Journal of Pharmacology and Experimental Therapeutics 306 (1): 84–92. doi:10.1124/jpet.103.049809. PMID 12660311.
- Punke MA, Licher T, Pongs O, Friederich P (2003). "Inhibition of human TREK-1 channels by bupivacaine". Anesthesia & Analgesia 96 (6): 1665–73. doi:10.1213/01.ANE.0000062524.90936.1F. PMID 12760993.
- Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J (1996). "TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure". The EMBO Journal 15 (5): 1004–11. PMC 449995. PMID 8605869.
- Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M (1997). "TASK, a human background K+ channel to sense external pH variations near physiological pH". The EMBO Journal 16 (17): 5464–71. doi:10.1093/emboj/16.17.5464. PMC 1170177. PMID 9312005.
- Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M (1998). "Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney". The Journal of Biological Chemistry 273 (47): 30863–9. doi:10.1074/jbc.273.47.30863. PMID 9812978.
- Meadows HJ, Benham CD, Cairns W, Gloger I, Jennings C, Medhurst AD, Murdock P, Chapman CG (2000). "Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel". Pflügers Archiv : European Journal of Physiology 439 (6): 714–22. doi:10.1007/s004240050997. PMID 10784345.
- Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M (1999). "Inhalational anesthetics activate two-pore-domain background K+ channels". Nature Neuroscience 2 (5): 422–6. doi:10.1038/8084. PMID 10321245.
- Gray AT, Zhao BB, Kindler CH, Winegar BD, Mazurek MJ, Xu J, Chavez RA, Forsayeth JR, Yost CS (2000). "Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5". Anesthesiology 92 (6): 1722–30. doi:10.1097/00000542-200006000-00032. PMID 10839924.
- Rogawski MA, Bazil CW (July 2008). "New Molecular Targets for Antiepileptic Drugs: α2δ, SV2A, and Kv7/KCNQ/M Potassium Channels". Curr Neurol Neurosci Rep 8 (4): 345–52. doi:10.1007/s11910-008-0053-7. PMC 2587091. PMID 18590620.
- Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998). "The structure of the potassium channel: molecular basis of K+ conduction and selectivity". Science 280 (5360): 69–77. Bibcode:1998Sci...280...69D. doi:10.1126/science.280.5360.69. PMID 9525859.
- MacKinnon R, Cohen SL, Kuo A, Lee A, Chait BT (1998). "Structural conservation in prokaryotic and eukaryotic potassium channels". Science 280 (5360): 106–9. Bibcode:1998Sci...280..106M. doi:10.1126/science.280.5360.106. PMID 9525854.
- Armstrong C (1998). "The vision of the pore". Science 280 (5360): 56–7. doi:10.1126/science.280.5360.56. PMID 9556453.
- "The Nobel Prize in Chemistry 2003". The Nobel Foundation. Retrieved 2007-11-16.
- Zhou Y, Morais-Cabral JH, Kaufman A, MacKinnon R (2001). "Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 Â resolution". Nature 414 (6859): 43–8. doi:10.1038/35102009. PMID 11689936.
- Hellgren M, Sandberg L, Edholm O (2006). "A comparison between two prokaryotic potassium channels (KirBac1.1 and KcsA) in a molecular dynamics (MD) simulation study". Biophys. Chem. 120 (1): 1–9. doi:10.1016/j.bpc.2005.10.002. PMID 16253415.
- Noskov SY, Roux B (Feb 2007). "Importance of hydration and dynamics on the selectivity of the KcsA and NaK channels.". The Journal of General Physiology 129 (2): 135–43. doi:10.1085/jgp.200609633. PMC 2154357. PMID 17227917.
- Noskov SY, Bernèche S, Roux B (Oct 14, 2004). "Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands.". Nature 431 (7010): 830–4. doi:10.1038/nature02943. PMID 15483608.
- Varma S, Rempe SB (Aug 15, 2007). "Tuning ion coordination architectures to enable selective partitioning.". Biophysical Journal 93 (4): 1093–9. doi:10.1529/biophysj.107.107482. PMC 1929028. PMID 17513348.
- Thomas M, Jayatilaka D, Corry B (Oct 15, 2007). "The predominant role of coordination number in potassium channel selectivity.". Biophysical Journal 93 (8): 2635–43. doi:10.1529/biophysj.107.108167. PMC 1989715. PMID 17573427.
- Bostick DL, Brooks CL (May 29, 2007). "Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state.". Proceedings of the National Academy of Sciences of the United States of America 104 (22): 9260–5. doi:10.1073/pnas.0700554104. PMC 1890482. PMID 17519335.
- Derebe MG, Sauer DB, Zeng W, Alam A, Shi N, Jiang Y (Jan 11, 2011). "Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites.". Proceedings of the National Academy of Sciences of the United States of America 108 (2): 598–602. doi:10.1073/pnas.1013636108. PMC 3021048. PMID 21187421.
- Morais-Cabral JH, Zhou Y, MacKinnon R (Nov 1, 2001). "Energetic optimization of ion conduction rate by the K+ selectivity filter.". Nature 414 (6859): 37–42. doi:10.1038/35102000. PMID 11689935.
- Yuan P, Leonetti MD, Pico AR, Hsiung Y, MacKinnon R (Jul 9, 2010). "Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution.". Science 329 (5988): 182–6. doi:10.1126/science.1190414. PMC 3022345. PMID 20508092.
- Wu Y, Yang Y, Ye S, Jiang Y (Jul 15, 2010). "Structure of the gating ring from the human large-conductance Ca(2+)-gated K(+) channel.". Nature 466 (7304): 393–7. doi:10.1038/nature09252. PMC 2910425. PMID 20574420.
- Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R (Mar 2001). "Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel.". Neuron 29 (3): 593–601. doi:10.1016/S0896-6273(01)00236-7. PMID 11301020.
- Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R (May 30, 2002). "Crystal structure and mechanism of a calcium-gated potassium channel.". Nature 417 (6888): 515–22. doi:10.1038/417515a. PMID 12037559.
- Uysal S, Cuello LG, Cortes DM, Koide S, Kossiakoff AA, Perozo E (Jul 19, 2011). "Mechanism of activation gating in the full-length KcsA K+ channel.". Proceedings of the National Academy of Sciences of the United States of America 108 (29): 11896–9. doi:10.1073/pnas.1105112108. PMC 3141920. PMID 21730186.
- Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R (May 1, 2003). "X-ray structure of a voltage-dependent K+ channel.". Nature 423 (6935): 33–41. doi:10.1038/nature01580. PMID 12721618.
- Long SB, Campbell EB, Mackinnon R (Aug 5, 2005). "Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.". Science 309 (5736): 897–903. doi:10.1126/science.1116269. PMID 16002581.
- Antz C, Fakler B (Aug 1998). "Fast Inactivation of Voltage-Gated K(+) Channels: From Cartoon to Structure.". News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society 13: 177–182. PMID 11390785.
- Cheng, W. W. L.; McCoy, J. G.; Thompson, A. N.; Nichols, C. G.; Nimigean, C. M. (2011). "Mechanism for selectivity-inactivation coupling in KcsA potassium channels". Proceedings of the National Academy of Sciences 108 (13): 5272. doi:10.1073/pnas.1014186108. PMC 3069191. PMID 21402935.
- Cuello LG, Jogini V, Cortes DM, Perozo E (Jul 8, 2010). "Structural mechanism of C-type inactivation in K(+) channels.". Nature 466 (7303): 203–8. doi:10.1038/nature09153. PMC 3033749. PMID 20613835.
- Cuello LG, Jogini V, Cortes DM, Pan AC, Gagnon DG, Dalmas O, Cordero-Morales JF, Chakrapani S, Roux B, Perozo E (Jul 8, 2010). "Structural basis for the coupling between activation and inactivation gates in K(+) channels.". Nature 466 (7303): 272–5. doi:10.1038/nature09136. PMC 3033755. PMID 20613845.
- Judge SI, Bever CT (July 2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacol. Ther. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864.
- Luzhkov VB, Aqvist J (14 February 2005). "Ions and blockers in potassium channels: insights from free energy simulations". Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 1747 (1): 109–120. doi:10.1016/j.bbapap.2004.10.006. PMID 15680245.
- Luzhkov, Victor B.; Fredrik Osterberg; Johan Aqvist (26 September 2003). "Structure–activity relationship for extracellular block of K+ channels by tetraalkylammonium ions". FEBS Letter 554 (1–2): 159–164. doi:10.1016/S0014-5793(03)01117-7.
- Krapivinsky G, Gordon EA, Wickman K, Velimirović B, Krapivinsky L, Clapham DE (1995). "The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K+-channel proteins". Nature 374 (6518): 135–41. Bibcode:1995Natur.374..135K. doi:10.1038/374135a0. PMID 7877685.
- Corey S, Krapivinsky G, Krapivinsky L, Clapham DE (1998). "Number and stoichiometry of subunits in the native atrial G-protein-gated K+ channel, IKACh". J. Biol. Chem. 273 (9): 5271–8. doi:10.1074/jbc.273.9.5271. PMID 9478984.
- Kunkel MT, Peralta EG (1995). "Identification of domains conferring G protein regulation on inward rectifier potassium channels". Cell 83 (3): 443–9. doi:10.1016/0092-8674(95)90122-1. PMID 8521474.
- Wickman K, Krapivinsky G, Corey S, Kennedy M, Nemec J, Medina I, Clapham DE (1999). "Structure, G protein activation, and functional relevance of the cardiac G protein-gated K+ channel, IKACh". Ann. N. Y. Acad. Sci. 868 (1): 386–98. Bibcode:1999NYASA.868..386W. doi:10.1111/j.1749-6632.1999.tb11300.x. PMID 10414308.
- 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.
- Proteopedia Potassium_channel in 3D
- Potassium Channels at the US National Library of Medicine Medical Subject Headings (MeSH)
- Neuromuscular Disease Center (2008-03-04). "Potassium Channels". Washington University in St. Louis. Retrieved 2008-03-10.
- UMich Orientation of Proteins in Membranes families/superfamily-8