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{{Short description|Group of transmembrane proteins that passively transport potassium ions}}
{{Infobox protein family
| Symbol = IRK
| Name = Inward rectifier potassium channel
| image =
| width =
| caption = crystal structure of an inward rectifier potassium channel
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| TCDB = 1.A.2
| OPM family = 8
| OPM protein =
| CAZy =
| CDD =
}}
'''Inward-rectifier potassium channels''' ('''K<sub>ir</sub>''', '''IRK''') are a specific [[Lipid-gated_ion_channels|lipid-gated]] subset of [[potassium channel]]s. To date, seven subfamilies have been identified in various mammalian cell types,<ref name="Kubo">{{cite journal | vauthors = Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA | display-authors = 6 | title = International Union of Pharmacology. LIV. Nomenclature and Molecular Relationships of Inwardly Rectifying Potassium Channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 509–26 | date = December 2005 | pmid = 16382105 | doi = 10.1124/pr.57.4.11 | s2cid = 11588492 | authorlink8 = Colin Nichols }}</ref> plants,<ref name="pmid8582318">{{cite journal | vauthors = Hedrich R, Moran O, Conti F, Busch H, Becker D, Gambale F, Dreyer I, Küch A, Neuwinger K, Palme K | display-authors = 6 | title = Inward rectifier potassium channels in plants differ from their animal counterparts in response to voltage and channel modulators | journal = European Biophysics Journal | volume = 24 | issue = 2 | pages = 107–15 | year = 1995 | pmid = 8582318 | doi = 10.1007/BF00211406 | s2cid = 12718513 }}</ref> and bacteria.<ref name="tcdb.org">{{Cite web|url = http://www.tcdb.org/search/result.php?tc=1.A.2|title = 1.A.2 Inward Rectifier K Channel (IRK-C) Family|website = TCDB|access-date = 2016-04-09}}</ref> They are
▲'''Inward-rectifier potassium channels''' ('''K<sub>ir</sub>''', '''IRK''') are a specific subset of [[potassium channel]]s. To date, seven subfamilies have been identified in various mammalian cell types,<ref name="Kubo">{{cite journal | vauthors = Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA | title = International Union of Pharmacology. LIV. Nomenclature and Molecular Relationships of Inwardly Rectifying Potassium Channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 509–26 | date = December 2005 | pmid = 16382105 | doi = 10.1124/pr.57.4.11 | authorlink8 = Colin Nichols }}</ref> plants,<ref name="pmid8582318">{{cite journal | vauthors = Hedrich R, Moran O, Conti F, Busch H, Becker D, Gambale F, Dreyer I, Küch A, Neuwinger K, Palme K | title = Inward rectifier potassium channels in plants differ from their animal counterparts in response to voltage and channel modulators | journal = European Biophysics Journal | volume = 24 | issue = 2 | pages = 107–15 | year = 1995 | pmid = 8582318 | doi = 10.1007/BF00211406 }}</ref> and bacteria.<ref name="tcdb.org">{{Cite web|url = http://www.tcdb.org/search/result.php?tc=1.A.2|title = 1.A.2 Inward Rectifier K Channel (IRK-C) Family|website = TCDB|access-date = 2016-04-09}}</ref> They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.<ref name="Abraham">{{cite journal | vauthors = Abraham MR, Jahangir A, Alekseev AE, Terzic A | title = Channelopathies of inwardly rectifying potassium channels | journal = FASEB Journal | volume = 13 | issue = 14 | pages = 1901–10 | date = November 1999 | pmid = 10544173 | url = http://www.fasebj.org/cgi/content/full/13/14/1901 | doi = 10.1096/fasebj.13.14.1901 }}</ref> IRK channels possess a pore domain, homologous to that of [[voltage-gated ion channel]]s, and flanking [[transmembrane domain |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|potassium (K<sup>+</sup>)]], with a greater tendency for K<sup>+</sup> uptake than K<sup>+</sup> export.<ref name="tcdb.org"/>
==Overview of inward rectification==
[[File:Inward-rectification.png|thumb|right|400px|'''Figure 1.''' [[Patch clamp#Whole-cell recording or whole-cell patch|Whole-cell current recordings]] of K<sub>ir</sub>2 inwardly-rectifying potassium channels expressed in an [[HEK cell|HEK293 cell]]. (This is a strongly inwardly rectifying current. Downward deflections are inward currents, upward deflections outward currents, and the x-axis is time in seconds.) There are 13 responses superimposed in this image. The bottom-most trace is [[ampere|current]] elicited by a voltage step to
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.
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==Activation by PIP<sub>2</sub>==
All K<sub>ir</sub> channels require [[phosphatidylinositol 4,5-bisphosphate]] (PIP<sub>2</sub>) for activation.<ref name="pmid18411329">{{cite journal | vauthors = Tucker SJ, Baukrowitz T | title = How highly charged anionic lipids bind and regulate ion channels | journal = The Journal of General Physiology | volume = 131 | issue = 5 | pages = 431–8 | date = May 2008 | pmid = 18411329 | pmc = 2346576 | doi = 10.1085/jgp.200709936 }}</ref> PIP<sub>2</sub> binds to
==Role
K<sub>ir</sub> channels are found in multiple cell types, including [[macrophages]], [[cardiac]] and [[kidney]] cells, [[leukocytes]], [[neurons]], and [[endothelial cells]]. By mediating a small [[depolarization|depolarizing]] K<sup>+</sup> current at negative membrane potentials, they help establish resting membrane potential, and in the case of the [[G protein-coupled inwardly-rectifying potassium channel|K<sub>ir</sub>3]] group, they help mediate inhibitory [[neurotransmitter]] responses, but their roles in cellular physiology vary across cell types:
{| class="wikitable"
|-
| [[Cardiac muscle cell|cardiac myocytes]] || K<sub>ir</sub> channels close upon depolarization, slowing membrane repolarization and helping maintain a more prolonged [[cardiac action potential]].
|-
| [[endothelial cell]]s || K<sub>ir</sub> channels are involved in regulation of [[nitric oxide synthase]].
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| [[kidneys]] || K<sub>ir</sub> 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-coupled inwardly-rectifying potassium channel|G-protein activated IRKs (K<sub>ir</sub>3)]] are important regulators, modulated by neurotransmitters. A mutation in the [[KCNJ6|GIRK2]] channel leads to the weaver mouse mutation. "Weaver" mutant mice are ataxic and display a neuroinflammation-mediated degeneration of their dopaminergic neurons.<ref>{{cite journal | vauthors = Peng J, Xie L, Stevenson FF, Melov S, Di Monte DA, Andersen JK | title = Nigrostriatal dopaminergic neurodegeneration in the weaver mouse is mediated via neuroinflammation and alleviated by minocycline administration | journal = The Journal of Neuroscience | volume = 26 | issue = 45 | pages = 11644–51 | date = November 2006 | pmid = 17093086 | pmc = 6674792 | doi = 10.1523/JNEUROSCI.3447-06.2006 }}</ref> Relative to non-ataxic controls, Weaver mutants have deficits in motor coordination and changes in regional brain metabolism.<ref>{{cite journal | vauthors = Strazielle C, Deiss V, Naudon L, Raisman-Vozari R, Lalonde R | title = Regional brain variations of cytochrome oxidase activity and motor coordination in Girk2(Wv) (Weaver) mutant mice | journal = Neuroscience | volume = 142 | issue = 2 | pages = 437–49 | date = October 2006 | pmid = 16844307 | doi = 10.1016/j.neuroscience.2006.06.011 | s2cid = 33064439 }}</ref> Weaver mice have been examined in labs interested in neural development and disease for over 30 years.
|-
| pancreatic [[beta cell]]s || [[ATP-sensitive potassium channel|K<sub>ATP</sub> channels]] (composed of [[Kir6.2|K<sub>ir</sub>6.2]] and [[sulfonylurea receptor|SUR1]] subunits) control insulin release.
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== Regulation ==
Voltage-dependence may be regulated by external K<sup>+</sup>, by internal Mg<sup>2+</sup>, by internal [[Adenosine triphosphate|ATP]] and/or by [[G protein|G-proteins]]. The P domains of IRK channels exhibit limited sequence similarity to those of the
== Structure ==
The crystal structure<ref>{{cite journal | vauthors = Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA | display-authors = 6 | title = Crystal structure of the potassium channel KirBac1.1 in the closed state | journal = Science | volume = 300 | issue = 5627 | pages = 1922–6 | date = June 2003 | pmid = 12738871 | doi = 10.1126/science.1085028 | bibcode = 2003Sci...300.1922K | s2cid = 2703162 | doi-access = free }}</ref> and function<ref name=":0">{{cite journal | vauthors = Enkvetchakul D, Bhattacharyya J, Jeliazkova I, Groesbeck DK, Cukras CA, Nichols CG | title = Functional characterization of a prokaryotic Kir channel | journal = The Journal of Biological Chemistry | volume = 279 | issue = 45 | pages = 47076–80 | date = November 2004 | pmid = 15448150 | doi = 10.1074/jbc.C400417200 | pmc = 8629170 | doi-access = free }}</ref> 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 [[meglumine|''N''-methyl-<small>D</small>-glucamine]]). Activity is inhibited by Ba<sup>2+</sup>, Ca<sup>2+</sup>, and low pH.<ref name=":0" />
==Classification
There are seven subfamilies of K<sub>ir</sub> channels, denoted as K<sub>ir</sub>1
K<sub>ir</sub> channels are formed from as [[homotetrameric]] membrane proteins.
===Diversity===
{| class="sortable wikitable"
|-
| {{Gene|KCNJ1}} || [[ROMK|K<sub>ir</sub>1.1]] || ROMK1 || [[Sodium-hydrogen exchange regulatory cofactor 2|NHERF2]]
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*''[[Barium poisoning]]'' is likely due to its ability to block K<sub>ir</sub> channels.
*''[[Atherosclerosis]] (heart disease)'' may be related to K<sub>ir</sub> channels. The loss of K<sub>ir</sub> 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 K<sub>ir</sub>2.6 function.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis | journal = Cell | volume = 140 | issue = 1 | pages = 88–98 | date = January 2010 | pmid = 20074522 | pmc = 2885139 | doi = 10.1016/j.cell.2009.12.024 }}</ref>
*''[[EAST/SeSAME syndrome]]'' is caused by mutations in KCNJ10.<ref>{{cite journal | vauthors = Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van't Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R | display-authors = 6 | title = Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations | journal = The New England Journal of Medicine | volume = 360 | issue = 19 | pages = 1960–70 | date = May 2009 | pmid = 19420365 | pmc = 3398803 | doi = 10.1056/NEJMoa0810276 }}</ref>
== See also ==
* [[G protein-coupled inwardly-rectifying potassium channel]]
* [[Transporter Classification Database]]▼
* [[hERG]]
▲* [[Transporter Classification Database]]
== References ==
{{Reflist
== Further reading ==
{{refbegin}}
{{refend}}
== External links ==
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{{Ion channels|g3}}
{{channel blockers}}
{{DEFAULTSORT:Inward-Rectifier Potassium Ion Channel}}
[[Category:
[[Category:Electrophysiology]]
[[Category:Integral membrane proteins]]
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