Inward-rectifier potassium channel: Difference between revisions

'''Inward-rectifier potassium channels''' ('''K_ir''', '''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 activated by phosphatidylinositol 4,5-bisphosphate ([[Phosphatidylinositol 4,5-bisphosphate|PIP₂]]). The malfunction of the channels has been implicated in several diseases.<ref>{{cite journal |last1 vauthors = Hansen |first1=SB | title = Lipid agonism: The PIP2 paradigm of ligand-gated ion channels. | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |date=May 2015volume |volume= 1851 | issue = 5 | pages = 620–8 | date = May 2015 | pmid = 25633344 | pmc = 4540326 | doi = 10.1016/j.bbalip.2015.01.011 |pmid=25633344|pmc=4540326 }}</ref><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 | doi = 10.1096/fasebj.13.14.1901 | doi-access = free | s2cid = 22205168 }}</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-oligomer|homo-]] or [[Hetero-oligomers|heterooligomers]] and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport [[potassium|potassium (K⁺)]], with a greater tendency for K⁺ uptake than K⁺ export.<ref name="tcdb.org"/> The process of inward-rectification was discovered by [[Denis Noble]] in cardiac muscle cells in 1960s<ref>{{Cite journal |last=Noble |first=Denis |date=December 1965 |title=Electrical properties of cardiac muscle attributable to inward going (anomalous) rectification |url=https://onlinelibrary.wiley.com/doi/10.1002/jcp.1030660520 |journal=Journal of Cellular and Comparative Physiology |language=en |volume=66 |issue=S2 |pages=127–135 |doi=10.1002/jcp.1030660520 |issn=0095-9898}}</ref> and by [[Richard Adrian, 2nd Baron Adrian|Richard Adrian]] and [[Alan Lloyd Hodgkin|Alan Hodgkin]] in 1970 in skeletal muscle cells.<ref>{{cite journal | vauthors = Adrian RH, Chandler WK, Hodgkin AL | title = Slow changes in potassium permeability in skeletal muscle | journal = The Journal of Physiology | volume = 208 | issue = 3 | pages = 645–68 | date = July 1970 | pmid = 5499788 | pmc = 1348790 | doi = 10.1113/jphysiol.1970.sp009140 | pmc = 1348790 }}</ref>

All K_ir channels require [[phosphatidylinositol 4,5-bisphosphate]] (PIP₂) 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> PIP₂ binds to and directly activates K_ir 2.2 with agonist-like properties.<ref>{{cite journal | vauthors = Hansen SB, Tao X, MacKinnon R | title = Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2 | journal = Nature | volume = 477 | issue = 7365 | pages = 495–8 | date = SeptemberAugust 2011 | pmid = 21874019 | pmc = 3324908 | doi = 10.1038/nature10370 | bibcode = 2011Natur.477..495H }}</ref> In this regard K_ir channels are PIP₂ [[ligand-gated ion channels]].

==Role of K_ir channels==

K_ir 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⁺ 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_ir3]] group, they help mediate inhibitory [[neurotransmitter]] responses, but their roles in cellular physiology vary across cell types:

| [[Cardiac muscle cell|cardiac myocytes]] || K_ir 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 [[Voltage-gated potassium channel|delayed rectifier K⁺ channels]], which help repolarize nerve and muscle cells after [[action potential]]s; and [[Tandem pore domain potassium channel|potassium leak channels]], which provide much of the basis for the [[Resting potential|resting membrane potential]].

| [[neurons]] and in heart cells || [[G protein-coupled inwardly-rectifying potassium channel|G-protein activated IRKs (K_ir3)]] 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.

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 Ba²⁺, Ca²⁺, and low pH.<ref name=":0" />

==Classification of K_ir channels==

There are seven subfamilies of K_ir channels, denoted as K_ir1 -– K_ir7.<ref name="Kubo"/> Each subfamily has multiple members (i.e. K_ir2.1, K_ir2.2, K_ir2.3, etc.) that have nearly identical amino acid sequences across known mammalian species.

K_ir channels are formed from as [[homotetrameric]] membrane proteins. Each of the four identical protein subunits is composed of two membrane-spanning [[alpha helix|alpha helices]] (M1 and M2). Heterotetramers can form between members of the same subfamily (i.e. K_ir2.1 and K_ir2.3) when the channels are overexpressed.

*''[[Thyrotoxic hypokalaemic periodic paralysis]]'' has been linked to altered K_ir2.6 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>

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[[* {{cite book | vauthors = Hille B | author-link1 = Bertil Hille]] (| date = 2001). ''| title = Ion Channels of Excitable Membranes'' | edition = 3rd ed.| publisher = (Sinauer: | location = Sunderland, MA), pp.&nbsp;| pages = 149–154. {{ISBN| isbn = 0-87893-321-2}}.