Inward-rectifier potassium channel

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Inward rectifier potassium channel
TREK PIP2.png
crystal structure of an inward rectifier potassium channel
Identifiers
SymbolIRK
Pfam PF01007
Pfam clan CL0030
InterPro IPR013521
SCOP2 1n9p / SCOPe / SUPFAM
TCDB 1.A.2
OPM superfamily 8
OPM protein 3SPG
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, [1] plants, [2] and bacteria. [3] They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. [4] [5] 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. [3] The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s [6] and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells. [7]

Contents

Overview of inward rectification

Figure 1. Whole-cell current recordings of Kir2 inwardly-rectifying potassium channels expressed in an 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 current elicited by a voltage step to -60mV, and the top-most to +60mV, relative to the resting potential, which is close to the K reversal potential in this experimental system. Other traces are in 10mV increments between the two. Inward-rectification.png
Figure 1. Whole-cell current recordings of Kir2 inwardly-rectifying potassium channels expressed in an 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 current elicited by a voltage step to -60mV, and the top-most to +60mV, relative to the resting potential, which is close to the K reversal potential in this experimental system. Other traces are in 10mV increments between the two.

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. [8]

Inward rectifiers also differ from tandem pore domain potassium channels, which are largely responsible for "leak" K+ currents. [9] 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). [10]

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. [11]

Activation by PIP2

All Kir channels require phosphatidylinositol 4,5-bisphosphate (PIP2) for activation. [12] PIP2 binds to and directly activates Kir 2.2 with agonist-like properties. [13] In this regard Kir channels are PIP2 ligand-gated ion channels.

Role

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:

LocationFunction
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. [14] Relative to non-ataxic controls, Weaver mutants have deficits in motor coordination and changes in regional brain metabolism. [15] 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.

Regulation

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. [16]

Structure

The crystal structure [17] and function [18] 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. [18]

Classification

There are seven subfamilies of Kir channels, denoted as Kir1 – Kir7. [1] 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.

Diversity

GeneProteinAliasesAssociated subunits
KCNJ1 Kir1.1 ROMK1 NHERF2
KCNJ2 Kir2.1 IRK1Kir2.2, Kir4.1, PSD-95, SAP97, AKAP79
KCNJ12 Kir2.2 IRK2Kir2.1 and Kir2.3 to form heteromeric channel, auxiliary subunit: SAP97, Veli-1, Veli-3, PSD-95
KCNJ4 Kir2.3 IRK3Kir2.1 and Kir2.3 to form heteromeric channel, PSD-95, Chapsyn-110/PSD-93
KCNJ14 Kir2.4 IRK4Kir2.1 to form heteromeric channel
KCNJ3 Kir3.1 GIRK1, KGAKir3.2, Kir3.4, Kir3.5, Kir3.1 is not functional by itself
KCNJ6 Kir3.2 GIRK2Kir3.1, Kir3.3, Kir3.4 to form heteromeric channel
KCNJ9 Kir3.3 GIRK3Kir3.1, Kir3.2 to form heteromeric channel
KCNJ5 Kir3.4 GIRK4Kir3.1, Kir3.2, Kir3.3
KCNJ10 Kir4.1 Kir1.2Kir4.2, Kir5.1, and Kir2.1 to form heteromeric channels
KCNJ15 Kir4.2 Kir1.3
KCNJ16 Kir5.1 BIR 9
KCNJ8 Kir6.1 KATP SUR2B
KCNJ11 Kir6.2 KATP SUR1, SUR2A, and SUR2B
KCNJ13 Kir7.1 Kir1.4

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">Cardiac action potential</span> Biological process in the heart

The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.

<span class="mw-page-title-main">Potassium channel</span> Ion channel that selectively passes K+

Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cell functions.

K<sub>ir</sub>2.1 Protein-coding gene in the species Homo sapiens

The Kir2.1 inward-rectifier potassium channel is a lipid-gated ion channel encoded by the KCNJ2 gene.

An ATP-sensitive potassium channel is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. KATP channels are widely distributed in plasma membranes; however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").

K<sub>ir</sub>6.2 Protein-coding gene in the species Homo sapiens

Kir6.2 is a major subunit of the ATP-sensitive K+ channel, a lipid-gated inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.

<span class="mw-page-title-main">KCNJ4</span> Protein-coding gene in the species Homo sapiens

Potassium inwardly-rectifying channel, subfamily J, member 4, also known as KCNJ4 or Kir2.3, is a human gene.

<span class="mw-page-title-main">KCNJ8</span> Protein-coding gene in humans

Potassium inwardly-rectifying channel, subfamily J, member 8, also known as KCNJ8, is a human gene encoding the Kir6.1 protein. A mutation in KCNJ8 has been associated with cardiac arrest in the early repolarization syndrome.

<span class="mw-page-title-main">KCNJ12</span> Protein-coding gene in the species Homo sapiens

ATP-sensitive inward rectifier potassium channel 12 is a lipid-gated ion channel that in humans is encoded by the KCNJ12 gene.

<span class="mw-page-title-main">KCNJ10</span> Protein-coding gene in the species Homo sapiens

ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.

<span class="mw-page-title-main">KCNJ15</span> Protein-coding gene in the species Homo sapiens

Potassium inwardly-rectifying channel, subfamily J, member 15, also known as KCNJ15 is a human gene, which encodes the Kir4.2 protein.

<span class="mw-page-title-main">LIN7B</span> Protein-coding gene in humans

Lin-7 homolog B is a protein that in humans is encoded by the LIN7B gene.

<span class="mw-page-title-main">KCNJ16</span> Protein-coding gene in the species Homo sapiens

Potassium inwardly-rectifying channel, subfamily J, member 16 (KCNJ16) is a human gene encoding the Kir5.1 protein.

<span class="mw-page-title-main">KCNJ14</span> Protein-coding gene in the species Homo sapiens

Potassium inwardly-rectifying channel, subfamily J, member 14 (KCNJ14), also known as Kir2.4, is a human gene.

The G protein-coupled inwardly rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs in turn release activated G-protein βγ- subunits (Gβγ) from inactive heterotrimeric G protein complexes (Gαβγ). Finally, the Gβγ dimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell membrane. G protein-coupled inwardly rectifying potassium channels are a type of G protein-gated ion channels because of this direct interaction of G protein subunits with GIRK channels. The activation likely works by increasing the affinity of the channel for PIP2. In high concentration PIP2 activates the channel absent G-protein, but G-protein does not activate the channel absent PIP2.

<span class="mw-page-title-main">Tertiapin</span>

Tertiapin is a 21-amino acid peptide isolated from venom of the European honey bee. It blocks two different types of potassium channels, inward rectifier potassium channels (Kir) and calcium activated large conductance potassium channels (BK).

<span class="mw-page-title-main">Lq2</span>

Lq2 is a component of the venom of the scorpion Leiurus quinquestriatus. It blocks various potassium channels, among others the inward-rectifier potassium ion channel ROMK1.

The Kir2.6 also known as inward rectifier potassium channel 18 is a protein that in humans is encoded by the KCNJ18 gene. Kir2.6 is an inward-rectifier potassium ion channel.

<span class="mw-page-title-main">Lipid-gated ion channels</span> Type of ion channel transmembrane protein

Lipid-gated ion channels are a class of ion channels whose conductance of ions through the membrane depends directly on lipids. Classically the lipids are membrane resident anionic signaling lipids that bind to the transmembrane domain on the inner leaflet of the plasma membrane with properties of a classic ligand. Other classes of lipid-gated channels include the mechanosensitive ion channels that respond to lipid tension, thickness, and hydrophobic mismatch. A lipid ligand differs from a lipid cofactor in that a ligand derives its function by dissociating from the channel while a cofactor typically derives its function by remaining bound.

AsKC11 is a toxin found in the venom of the sea anemone, Anemonia sulcata. This toxin is part of the Kunitz peptide family and has been shown to be an activator of G protein-coupled inwardly-rectifying potassium (GIRK) channels 1/2, involved in the regulation of cellular excitability. 

References

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  2. ↑ Hedrich R, Moran O, Conti F, Busch H, Becker D, Gambale F, et al. (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. doi:10.1007/BF00211406. PMID   8582318. S2CID   12718513.
  3. 1 2 "1.A.2 Inward Rectifier K Channel (IRK-C) Family". TCDB. Retrieved 2016-04-09.
  4. ↑ Hansen SB (May 2015). "Lipid agonism: The PIP2 paradigm of ligand-gated ion channels". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (5): 620–8. doi:10.1016/j.bbalip.2015.01.011. PMC   4540326 . PMID   25633344.
  5. ↑ Abraham MR, Jahangir A, Alekseev AE, Terzic A (November 1999). "Channelopathies of inwardly rectifying potassium channels". FASEB Journal. 13 (14): 1901–10. doi:10.1096/fasebj.13.14.1901. PMID   10544173. S2CID   22205168.
  6. ↑ Noble, Denis (December 1965). "Electrical properties of cardiac muscle attributable to inward going (anomalous) rectification". Journal of Cellular and Comparative Physiology. 66 (S2): 127–135. doi:10.1002/jcp.1030660520. ISSN   0095-9898.
  7. ↑ Adrian RH, Chandler WK, Hodgkin AL (July 1970). "Slow changes in potassium permeability in skeletal muscle". The Journal of Physiology. 208 (3): 645–68. doi:10.1113/jphysiol.1970.sp009140. PMC   1348790 . PMID   5499788.
  8. ↑ Bertil Hille (2001). Ion Channels of Excitable Membranes 3rd ed. (Sinauer: Sunderland, MA), p. 151. ISBN   0-87893-321-2.
  9. ↑ Hille, p. 155.
  10. ↑ Hille, p. 153.
  11. ↑ 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. doi:10.1085/jgp.106.5.923. PMC   2229292 . PMID   8648298.
  12. ↑ 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. doi:10.1085/jgp.200709936. PMC   2346576 . PMID   18411329.
  13. ↑ Hansen SB, Tao X, MacKinnon R (August 2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2". Nature. 477 (7365): 495–8. Bibcode:2011Natur.477..495H. doi:10.1038/nature10370. PMC   3324908 . PMID   21874019.
  14. ↑ 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. doi:10.1523/JNEUROSCI.3447-06.2006. PMC   6674792 . PMID   17093086.
  15. ↑ 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. doi:10.1016/j.neuroscience.2006.06.011. PMID   16844307. S2CID   33064439.
  16. ↑ WOapplication 0190360,Wei MH, Chaturvedi K, Guegler K, Webster M, Ketchum KA, Di Francesco V, Beasley E,"Isolated human transporter proteins, nucleic acid molecules encoding human transporter proteins, and uses thereof",published 29 November 2001, assigned to Apperla Corporation
  17. ↑ Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, et al. (June 2003). "Crystal structure of the potassium channel KirBac1.1 in the closed state". Science. 300 (5627): 1922–6. Bibcode:2003Sci...300.1922K. doi: 10.1126/science.1085028 . PMID   12738871. S2CID   2703162.
  18. 1 2 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. doi: 10.1074/jbc.C400417200 . PMC   8629170 . PMID   15448150.
  19. ↑ Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, et al. (January 2010). "Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis". Cell. 140 (1): 88–98. doi:10.1016/j.cell.2009.12.024. PMC   2885139 . PMID   20074522.
  20. ↑ Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, et al. (May 2009). "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations". The New England Journal of Medicine. 360 (19): 1960–70. doi:10.1056/NEJMoa0810276. PMC   3398803 . PMID   19420365.

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