Summary: Inward rectifier potassium channel
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Inward-rectifier potassium ion channel Edit Wikipedia article
|Inward rectifier potassium channel|
crystal structure of an inward rectifier potassium channel
|Inward rectifier potassium channel N-terminal|
Inwardly rectifying potassium channels (Kir, IRK) are a specific subset of potassium (K+) selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export.
Overview of inward rectification
A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell.
By convention, inward current (positive charge moving into the cell) is displayed in voltage clamp as a downward deflection, while an outward current (positive charge moving out of the cell) is shown as an upward deflection. At membrane potentials negative to potassium's reversal potential, inwardly rectifying K+ channels support the flow of positively charged K+ ions into the cell, pushing the membrane potential back to the resting potential. This can be seen in figure 1: when the membrane potential is clamped negative to the channel's resting potential (e.g. -60 mV), inward current flows (i.e. positive charge flows into the cell). However, when the membrane potential is set positive to the channel's resting potential (e.g. +60 mV), these channels pass very little current. Simply put, this channel passes much more current in the inward direction than the outward one, at its operating voltage range. These channels are not perfect rectifiers, as they can pass some outward current in the voltage range up to about 30 mV above resting potential.
These channels differ from the potassium channels that are typically responsible for repolarizing a cell following an action potential, such as the delayed rectifier and A-type potassium channels. Those more "typical" potassium channels preferentially carry outward (rather than inward) potassium currents at depolarized membrane potentials, and may be thought of as "outwardly rectifying." When first discovered, inward rectification was named "anomalous rectification" to distinguish it from outward potassium currents.
Inward rectifiers also differ from tandem pore domain potassium channels, which are largely responsible for "leak" K+ currents. Some inward rectifiers, termed "weak inward rectifiers", carry measurable outward K+ currents at voltages positive to the K+ reversal potential (corresponding to, but larger than, the small currents above the 0 nA line in figure 1). They, along with the "leak" channels, establish the resting membrane potential of the cell. Other inwardly rectifying channels, termed "strong inward rectifiers," carry very little outward current at all, and are mainly active at voltages negative to the K+ reversal potential, where they carry inward current (the much larger currents below the 0 nA line in figure 1).
Mechanism of inward rectification
The phenomenon of inward rectification of Kir channels is the result of high-affinity block by endogenous polyamines, namely spermine, as well as magnesium ions, that plug the channel pore at positive potentials, resulting in a decrease in outward currents. This voltage-dependent block by polyamines results in efficient conduction of current only in the inward direction. While the principal idea of polyamine block is understood, the specific mechanisms are still controversial.
Activation by PIP2
All Kir channels require phosphatidylinositol 4,5-bisphosphate (PIP2) for activation. PIP2 binds to and directly activates Kir 2.2 with agonist-like properties. In this regard Kir channels are PIP2 ligand-gated ion channels.
Role of Kir channels
Kir channels are found in multiple cell types, including macrophages, cardiac and kidney cells, leukocytes, neurons, and endothelial cells. By mediating a small depolarizing K+ current at negative membrane potentials, they help establish resting membrane potential, and in the case of the Kir3 group, they help mediate inhibitory neurotransmitter responses, but their roles in cellular physiology vary across cell types:
|cardiac myocytes||Kir channels close upon depolarization, slowing membrane repolarization and helping maintain a more prolonged cardiac action potential. This type of inward-rectifier channel is distinct from delayed rectifier K+ channels, which help repolarize nerve and muscle cells after action potentials; and potassium leak channels, which provide much of the basis for the resting membrane potential.|
|endothelial cells||Kir channels are involved in regulation of nitric oxide synthase.|
|kidneys||Kir export surplus potassium into collecting tubules for removal in the urine, or alternatively may be involved in the reuptake of potassium back into the body.|
|neurons and in heart cells||G-protein activated IRKs (Kir3) are important regulators, modulated by neurotransmitters. A mutation in the GIRK2 channel leads to the weaver mouse mutation. "Weaver" mutant mice are ataxic and display a neuroinflammation-mediated degeneration of their dopaminergic neurons. Relative to non-ataxic controls, Weaver mutants have deficits in motor coordination and changes in regional brain metabolism. Weaver mice have been examined in labs interested in neural development and disease for over 30 years.|
|pancreatic beta cells||KATP channels (composed of Kir6.2 and SUR1 subunits) control insulin release.|
Voltage-dependence may be regulated by external K+, by internal Mg2+, by internal ATP and/or by G-proteins. The P domains of IRK channels exhibit limited sequence similarity to those of the VIC family. Inward rectifiers play a role in setting cellular membrane potentials, and closing of these channels upon depolarization permits the occurrence of long duration action potentials with a plateau phase. Inward rectifiers lack the intrinsic voltage sensing helices found in many VIC family channels. In a few cases, those of Kir1.1a, Kir6.1 and Kir6.2, for example, direct interaction with a member of the ABC superfamily has been proposed to confer unique functional and regulatory properties to the heteromeric complex, including sensitivity to ATP. These ATP-sensitive channels are found in many body tissues. They render channel activity responsive to the cytoplasmic ATP/ADP ratio (increased ATP/ADP closes the channel). The human SUR1 and SUR2 sulfonylurea receptors (spQ09428 and Q15527, respectively) are the ABC proteins that regulate both the Kir6.1 and Kir6.2 channels in response to ATP, and CFTR (TC #3.A.1.208.4) may regulate Kir1.1a.
The crystal structure and function of bacterial members of the IRK-C family have been determined. KirBac1.1, from Burkholderia pseudomallei, is 333 amino acyl residues (aas) long with two N-terminal TMSs flanking a P-loop (residues 1-150), and the C-terminal half of the protein is hydrophilic. It transports monovalent cations with the selectivity: K ≈ Rb ≈ Cs ≫ Li ≈ Na ≈ NMGM (protonated N-methyl-D-glucamine). Activity is inhibited by Ba2+, Ca2+, and low pH.
Classification of Kir channels
There are seven subfamilies of Kir channels, denoted as Kir1 - Kir7. Each subfamily has multiple members (i.e. Kir2.1, Kir2.2, Kir2.3, etc.) that have nearly identical amino acid sequences across known mammalian species.
Kir channels are formed from as homotetrameric membrane proteins. Each of the four identical protein subunits is composed of two membrane-spanning alpha helices (M1 and M2). Heterotetramers can form between members of the same subfamily (i.e. Kir2.1 and Kir2.3) when the channels are overexpressed.
|KCNJ2||Kir2.1||IRK1||Kir2.2, Kir4.1, PSD-95, SAP97, AKAP79|
|KCNJ12||Kir2.2||IRK2||Kir2.1 and Kir2.3 to form heteromeric channel, auxiliary subunit: SAP97, Veli-1, Veli-3, PSD-95|
|KCNJ4||Kir2.3||IRK3||Kir2.1 and Kir2.3 to form heteromeric channel, PSD-95, Chapsyn-110/PSD-93|
|KCNJ14||Kir2.4||IRK4||Kir2.1 to form heteromeric channel|
|KCNJ3||Kir3.1||GIRK1, KGA||Kir3.2, Kir3.4, Kir3.5, Kir3.1 is not functional by itself|
|KCNJ6||Kir3.2||GIRK2||Kir3.1, Kir3.3, Kir3.4 to form heteromeric channel|
|KCNJ9||Kir3.3||GIRK3||Kir3.1, Kir3.2 to form heteromeric channel|
|KCNJ5||Kir3.4||GIRK4||Kir3.1, Kir3.2, Kir3.3|
|KCNJ10||Kir4.1||Kir1.2||Kir4.2, Kir5.1, and Kir2.1 to form heteromeric channels|
|KCNJ11||Kir6.2||KATP||SUR1, SUR2A, and SUR2B|
- Persistent hyperinsulinemic hypoglycemia of infancy is related to autosomal recessive mutations in Kir6.2. Certain mutations of this gene diminish the channel's ability to regulate insulin secretion, leading to hypoglycemia.
- Bartter's syndrome can be caused by mutations in Kir channels. This condition is characterized by the inability of kidneys to recycle potassium, causing low levels of potassium in the body.
- Andersen's syndrome is a rare condition caused by multiple mutations of Kir2.1. Depending on the mutation, it can be dominant or recessive. It is characterized by periodic paralysis, cardiac arrhythmias and dysmorphic features. (See also KCNJ2)
- Barium poisoning is likely due to its ability to block Kir channels.
- Atherosclerosis (heart disease) may be related to Kir channels. The loss of Kir currents in endothelial cells is one of the first known indicators of atherogenesis (the beginning of heart disease).
- Thyrotoxic hypokalaemic periodic paralysis has been linked to altered Kir2.6 function.
- EAST/SeSAME syndrome may be caused by mutations of KCNJ10.
- Potassium channel
- G protein-coupled inwardly-rectifying potassium channel
- Voltage-gated ion channel
- Transporter Classification Database
- Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA (December 2005). "International Union of Pharmacology. LIV. Nomenclature and Molecular Relationships of Inwardly Rectifying Potassium Channels". Pharmacological Reviews. 57 (4): 509–26. PMID 16382105. doi:10.1124/pr.57.4.11.
- Hedrich R, Moran O, Conti F, Busch H, Becker D, Gambale F, Dreyer I, Küch A, Neuwinger K, Palme K (1995). "Inward rectifier potassium channels in plants differ from their animal counterparts in response to voltage and channel modulators". European Biophysics Journal. 24 (2): 107–15. PMID 8582318. doi:10.1007/BF00211406.
- "1.A.2 Inward Rectifier K Channel (IRK-C) Family". TCDB. Retrieved 2016-04-09.
- Abraham MR, Jahangir A, Alekseev AE, Terzic A (November 1999). "Channelopathies of inwardly rectifying potassium channels". FASEB Journal. 13 (14): 1901–10. PMID 10544173.
- Bertil Hille (2001). Ion Channels of Excitable Membranes 3rd ed. (Sinauer: Sunderland, MA), p. 151. ISBN 0-87893-321-2.
- Hille, p. 155.
- Hille, p. 153.
- Lopatin AN, Makhina EN, Nichols CG (November 1995). "The mechanism of inward rectification of potassium channels: "long-pore plugging" by cytoplasmic polyamines". The Journal of General Physiology. 106 (5): 923–55. PMC . PMID 8648298. doi:10.1085/jgp.106.5.923.
- Tucker SJ, Baukrowitz T (May 2008). "How highly charged anionic lipids bind and regulate ion channels". The Journal of General Physiology. 131 (5): 431–8. PMC . PMID 18411329. doi:10.1085/jgp.200709936.
- Hansen SB, Tao X, MacKinnon R (September 2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2". Nature. 477 (7365): 495–8. PMC . PMID 21874019. doi:10.1038/nature10370.
- Peng J, Xie L, Stevenson FF, Melov S, Di Monte DA, Andersen JK (November 2006). "Nigrostriatal dopaminergic neurodegeneration in the weaver mouse is mediated via neuroinflammation and alleviated by minocycline administration". The Journal of Neuroscience. 26 (45): 11644–51. PMID 17093086. doi:10.1523/JNEUROSCI.3447-06.2006.
- Strazielle C, Deiss V, Naudon L, Raisman-Vozari R, Lalonde R (October 2006). "Regional brain variations of cytochrome oxidase activity and motor coordination in Girk2(Wv) (Weaver) mutant mice". Neuroscience. 142 (2): 437–49. PMID 16844307. doi:10.1016/j.neuroscience.2006.06.011.
- Wei, Ming-Hui; Chaturvedi, Kabir; Guegler, Karl; Webster, Marion; Ketchum, Karen A.; Di, Francesco Valentina; BEASLEY, Ellen § (Nov 29, 2001), Isolated human transporter proteins, nucleic acid molecules encoding human transporter proteins, and uses thereof, retrieved 2016-04-09
- Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA (June 2003). "Crystal structure of the potassium channel KirBac1.1 in the closed state". Science. 300 (5627): 1922–6. PMID 12738871. doi:10.1126/science.1085028.
- Enkvetchakul D, Bhattacharyya J, Jeliazkova I, Groesbeck DK, Cukras CA, Nichols CG (November 2004). "Functional characterization of a prokaryotic Kir channel". The Journal of Biological Chemistry. 279 (45): 47076–80. PMID 15448150. doi:10.1074/jbc.C400417200.
- Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, Jongjaroenprasert W, Liang MC, Khoo DH, Cheah JS, Ho SC, Bernstein HS, Maciel RM, Brown RH, Ptácek LJ (January 2010). "Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis". Cell. 140 (1): 88–98. PMC . PMID 20074522. doi:10.1016/j.cell.2009.12.024.
- Inward Rectifier Potassium Channels at the US National Library of Medicine Medical Subject Headings (MeSH).
- "Inwardly Recifying Potassium Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- UMich Orientation of Proteins in Membranes families/family-85 - Spatial positions of inward rectifier potassium channels in membranes.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR016449
Potassium channels are the most diverse group of the ion channel family [PUBMED:1772658, PUBMED:1879548]. They are important in shaping the action potential, and in neuronal excitability and plasticity [PUBMED:2451788]. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups [PUBMED:2555158]: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.
These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+ channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers [PUBMED:2448635]. In eukaryotic cells, K+ channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes [PUBMED:1373731]. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [PUBMED:11178249].
All K+ channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+ selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+ across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+ channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+ channels; and three types of calcium (Ca)-activated K+ channels (BK, IK and SK) [PUBMED:11178249]. The 2TM domain family comprises inward-rectifying K+ channels. In addition, there are K+ channel alpha-subunits that possess two P-domains. These are usually highly regulated K+ selective leak channels.
Inwardly-rectifying potassium channels (Kir) are the principal class of two-TM domain potassium channels. They are characterised by the property of inward-rectification, which is described as the ability to allow large inward currents and smaller outward currents. Inwardly rectifying potassium channels (Kir) are responsible for regulating diverse processes including: cellular excitability, vascular tone, heart rate, renal salt flow, and insulin release [PUBMED:10102275]. To date, around twenty members of this superfamily have been cloned, which can be grouped into six families by sequence similarity, and these are designated Kir1.x-6.x [PUBMED:7580148, PUBMED:10449331].
Cloned Kir channel cDNAs encode proteins of between ~370-500 residues, both N- and C-termini are thought to be cytoplasmic, and the N terminus lacks a signal sequence. Kir channel alpha subunits possess only 2TM domains linked with a P-domain. Thus, Kir channels share similarity with the fifth and sixth domains, and P-domain of the other families. It is thought that four Kir subunits assemble to form a tetrameric channel complex, which may be hetero- or homomeric [PUBMED:10102275].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||integral component of membrane (GO:0016021)|
|Molecular function||inward rectifier potassium channel activity (GO:0005242)|
|Biological process||potassium ion transport (GO:0006813)|
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This superfamily contains a diverse range of ion channels that share a pair of transmembrane helices in common. This clan is classified as the VIC (Voltage-gated Ion Channel) superfamily in TCDB.
The clan contains the following 7 members:Ion_trans Ion_trans_2 IRK KdpA Lig_chan PKD_channel TrkH
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|Seed source:||Pfam-B_18 (release 3.0)|
|Author:||Finn RD, Bateman A|
|Number in seed:||43|
|Number in full:||2563|
|Average length of the domain:||283.20 aa|
|Average identity of full alignment:||37 %|
|Average coverage of the sequence by the domain:||76.00 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
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We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 4 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IRK domain has been found. There are 82 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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