Top view of potassium ions (purple) moving through potassium channel (
PDB: 1BL8)
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.[1] 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.[2][3]
Contents
- 1 Function
- 2 Types
- 3 Structure
- 3.1 Selectivity filter
- 3.1.1 Selectivity mechanism
- 3.2 Hydrophobic region
- 3.3 Central cavity
- 4 Regulation
- 5 Blockers
- 6 Muscarinic potassium channel
- 7 In fine art
- 8 See also
- 9 References
- 10 External links
Function
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).[4] 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.
They also regulate cellular processes such as the secretion of hormones (e.g., insulin release from beta-cells in the pancreas) so their malfunction can lead to diseases (such as diabetes).
Types
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).
Potassium channel classes, function, and pharmacology.[5]
| Class |
Subclasses |
Function |
Blockers |
Activators |
Calcium-activated
6T & 1P |
- BK channel
- SK channel
- IK channel
|
- inhibition in response to rising intracellular calcium
|
- charybdotoxin, iberiotoxin
- apamin
|
|
Inwardly rectifying
2T & 1P |
|
- recycling and secretion of potassium in nephrons
|
|
|
|
|
- mediate the inhibitory effect of many GPCRs
|
- GPCR antagonists
- ifenprodil[6]
|
|
|
|
- close when ATP is high to promote insulin secretion
|
- glibenclamide
- tolbutamide
|
- diazoxide
- pinacidil
- minoxidil
- nicorandil
|
Tandem pore domain
4T & 2P |
- TWIK (TWIK-1, TWIK-2, KCNK7)[7][8]
- TREK (TREK-1, TREK-2, TRAAK[9])[7][8]
- TASK (TASK-1, TASK-3, TASK-5)[7][8]
- TALK (TASK-2,[10] TALK-1, TALK-2)[7][8]
- THIK (THIK-1, THIK-2)[7][8]
- TRESK[7][8][11][12]
|
- Contribute to resting potential
|
- bupivacaine[13][14][15][16]
- quinidine[14][17][18][19][20]
|
|
Voltage-gated
6T & 1P |
- hERG (Kv11.1)
- KvLQT1 (Kv7.1)
|
- action potential repolarization
- limits frequency of action potentials (disturbances cause dysrhythmia)
|
- tetraethylammonium
- 4-aminopyridine
- dendrotoxins (some types)
|
|
Structure
Potassium channel Kv1.2, structure in a membrane-like environment. Calculated hydrocarbon boundaries of the lipid bilayer are indicated by red and blue lines.
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,[24][25] profound insights have been gained into how potassium ions pass through these channels and why (smaller) sodium ions do not.[26] The 2003 Nobel Prize for Chemistry was awarded to Rod MacKinnon for his pioneering work in this area.[27]
Selectivity filter
Crystallographic structure of the bacterial KcsA potassium channel (PDB: 1K4C).[28] In this figure, only two of the four subunits of the tetramer are displayed for the sake of clarity. The protein is displayed as a green cartoon diagram. In addition backbone carbonyl groups and threonine sidechain protein atoms (oxygen = red, carbon = green) are displayed. Finally potassium ions (occupying the S2 and S4 sites) and the oxygen atoms of water molecules (S1 and S3) are depicted as purple and red spheres respectively.
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 electronegative carbonyl oxygen atoms aligned toward the center 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 center of the protein with the extracellular solution.[29]
Selectivity mechanism
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,[30] toy models of ion binding,[31] thermodynamic calculations,[32] topological considerations,[33][34] and structural differences[35] between selective and non-selective channels.
The mechanism for ion translocation in KcsA has been studied extensively by theoretical calculations and simulation.[29][36] 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.
Hydrophobic region
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.
Central cavity
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.
Regulation
Graphical representation of open and shut potassium channels (
PDB: 1lnq and
PDB: 1k4c). Two simple bacterial channels are shown to compare the "open" channel structure on the right with the "closed" structure on the left. At top is the filter (selects potassium ions), and at bottom is the gating domain (controls opening and closing of channel).
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 thought 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,[37][38][39] 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[40][41][42] and eukaryotic[37][38][39] channels, pH gating domain of KcsA,[43] cyclic nucleotide gating domains,[44] and voltage gated potassium channels.[45][46]
N-type inactivation is typically the faster inactivation mechanism, and is termed the "ball and chain" model.[47] 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 thought 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,[48][49][50] although the precise mechanism remains unclear.
Blockers
Potassium channel blockers inhibit the flow of potassium ions through the channel. They either compete with potassium binding within the selectivity filter or bind outside the filter to occlude ion conduction. An example of one of these competitors is quaternary ammonium ions, which bind at the extracellular face [51][52] or central cavity of the channel.[53] For blocking from the central cavity quaternary ammonium ions are also known as open channel blockers, as binding classically requires the prior opening of the cytoplasmic gate.[54]
Barium ions can also block potassium channel currents,[55][56] by binding with high affinity within the selectivity filter.[57][58][59][60] This tight binding is thought to underlie barium toxicity by inhibiting potassium channel activity in excitable cells.
Medically potassium channel blockers, such as 4-aminopyridine and 3,4-diaminopyridine, have been investigated for the treatment of conditions such as multiple sclerosis.[61] Off target drug effects can lead to drug induced Long QT syndrome, a potentially life threatening condition. This is most frequently due to action on the hERG potassium channel in the heart. Accordingly, all new drugs are preclinically tested for cardiac safety.
Muscarinic potassium channel
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.
See also: G protein-coupled inwardly-rectifying 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.[62][63] 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.[64][65]
In fine art
Roderick MacKinnon commissioned Birth of an Idea, a 5-foot (1.5 m) tall sculpture based on the KcsA potassium channel.[66] 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
- Inward-rectifier potassium ion channel
- Potassium transporter (Trk) family
- Potassium uptake permease
- Sodium ion channel
- Calcium channel
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- ^ Jiang Y, MacKinnon R (Mar 2000). "The barium site in a potassium channel by x-ray crystallography". The Journal of General Physiology. 115 (3): 269–72. doi:10.1085/jgp.115.3.269. PMC 2217209. PMID 10694255.
- ^ Lam YL, Zeng W, Sauer DB, Jiang Y (Aug 2014). "The conserved potassium channel filter can have distinct ion binding profiles: structural analysis of rubidium, cesium, and barium binding in NaK2K". The Journal of General Physiology. 144 (2): 181–92. doi:10.1085/jgp.201411191. PMC 4113894. PMID 25024267.
- ^ Guo R, Zeng W, Cui H, Chen L, Ye S (Aug 2014). "Ionic interactions of Ba2+ blockades in the MthK K+ channel". The Journal of General Physiology. 144 (2): 193–200. doi:10.1085/jgp.201411192. PMC 4113901. PMID 25024268.
- ^ Judge SI, Bever CT (Jul 2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacology & Therapeutics. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864.
- ^ Krapivinsky G, Gordon EA, Wickman K, Velimirović B, Krapivinsky L, Clapham DE (Mar 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 (Feb 1998). "Number and stoichiometry of subunits in the native atrial G-protein-gated K+ channel, IKACh". The Journal of Biological Chemistry. 273 (9): 5271–8. doi:10.1074/jbc.273.9.5271. PMID 9478984.
- ^ Kunkel MT, Peralta EG (Nov 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 (Apr 1999). "Structure, G protein activation, and functional relevance of the cardiac G protein-gated K+ channel, IKACh". Annals of the New York Academy of Sciences. 868 (1): 386–98. Bibcode:1999NYASA.868..386W. doi:10.1111/j.1749-6632.1999.tb11300.x. PMID 10414308.
- ^ Ball P (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
- Proteopedia channel 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
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Membrane transport protein: ion channels (TC 1A)
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Ca2+: Calcium channel
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|
| Ligand-gated |
- Inositol trisphosphate receptor
- Ryanodine receptor
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| Voltage-gated |
- L-type/Cavα
- N-type/Cavα2.2
- P-type/Cavα
- Q-type/Cavα2.1
- R-type/Cavα2.3
- T-type/Cavα
- α2δ-subunits
- β-subunits
- γ-subunits
- Cation channels of sperm
- Two-pore channel
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|
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Na+: Sodium channel
|
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| Constitutively active |
- Epithelial sodium channel
|
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| Proton-gated |
- Amiloride-sensitive cation channel
|
|
| Voltage-gated |
- Navα
- 1.1
- 1.2
- 1.3
- 1.4
- 1.5
- 1.6
- 1.7
- 1.8
- 1.9
- 7A
- Navβ
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K+: Potassium channel
|
|
| Calcium-activated |
- BK channel
- SK channel
- IK channel
- KCa
- 1.1
- 2.1
- 2.2
- 2.3
- 3.1
- 4.1
- 4.2
- 5.1
|
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| Inward-rectifier |
|
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| Tandem pore domain |
- K2P
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 9
- 10
- 12
- 13
- 15
- 16
- 17
- 18
|
|
| Voltage-gated |
- Kvα1-6
- 1.1
- 1.2
- 1.3
- 1.4
- 1.5
- 1.6
- 1.7
- 1.8
-
-
-
-
-
- Kvβ
- KCNIP
- minK/ISK
- minK/ISK-like
- MiRP
- Shaker gene
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Miscellaneous
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| Cl−: Chloride channel |
- Calcium-activated chloride channels
- Anoctamin
- Bestrophin
- Chloride Channel Accessory
- CFTR
- CLCN
- CLIC
- CLNS
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| H+: Proton channel |
|
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| M+: CNG cation channel |
|
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| M+: TRP cation channel |
- TRPA (1)
- TRPC
- TRPM
- TRPML
- TRPN
- TRPP
- TRPV
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| H2O (+ solutes): Porin |
- Aquaporin
- Voltage-dependent anion channel
- General bacterial porin family
|
|
| Cytoplasm: Gap junction |
- Connexin: A
- GJA1
- GJA3
- GJA4
- GJA5
- GJA8
- GJA9
- GJA10
- B
- GJB1
- GJB2
- GJB3
- GJB4
- GJB5
- GJB6
- GJB7
- C
- D
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By gating mechanism
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| Ion channel class |
- Ligand-gated
- Light-gated
- Voltage-gated
- Stretch-activated
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see also disorders
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